Indol-3-y-carbonyl-piperidin and piperazin-derivatives

ABSTRACT

The present invention relates to indol-3-yl-carbonyl-piperidin and piperazin derivatives which act as V1a receptor antagonists and which are represented by Formula I: 
     
       
         
         
             
             
         
       
     
     wherein the residues R 1  to R 3  are as defined herein. The invention also relates to pharmaceutical compositions containing such compounds, and methods for preparation of the compounds and compositions. The invention further relates to methods for treating dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders.

PRIORITY TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/779,099, filed May 13, 2010, now pending; which is a division of U.S.application Ser. No. 11/492,312, filed Jul. 25, 2006, now U.S. Pat. No.7,781,436, issued Aug. 24, 2010; which claims the benefit of EuropeanApplication Nos. 05107044.9, filed Jul. 29, 2005, and 05111072.4, filedNov. 22, 2005. The entire contents of the above-identified applicationsare hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Vasopressin is a 9 amino acid peptide mainly produced by theparaventricular nucleus of the hypothalamus. Three vasopressinreceptors, all belonging to the class I G-protein coupled receptors, areknown. The V1a receptor is expressed in the brain, liver, vascularsmooth muscle, lung, uterus and testis, the V1b or V3 receptor isexpressed in the brain and pituitary gland, the V2 receptor is expressedin the kidney where it regulates water excretion and mediates theantidiuretic effects of vasopressin.

In the periphery vasopressin acts as a neurohormone and stimulatesvasoconstriction, glycogenolysis and antidiuresis. In the brainvasopressin acts as a neuromodulator and is elevated in the amygdaladuring stress (Ebner, K., C. T. Wotjak, et al. (2002). “Forced swimmingtriggers vasopressin release within the amygdala to modulatestress-coping strategies in rats.” Eur J Neurosci 15(2): 384-8). The V1areceptor is extensively expressed in the brain and particularly inlimbic areas like the amygdala, lateral septum and hippocampus which areplaying an important role in the regulation of anxiety. Indeed V1aknock-out mouse show a reduction in anxiety behavior in the plus-maze,open field and light-dark box (Bielsky, I. F., S. B. Hu, et al. (2003).“Profound Impairment in Social Recognition and Reduction in Anxiety-LikeBehavior in Vasopressin V1a Receptor Knockout Mice.”Neuropsychopharmacology). The downregulation of the V1a receptor usingantisense oligonucleotide injection in the septum also causes areduction in anxiety behavior (Landgraf, R., R. Gerstberger, et al.(1995). “V1 vasopressin receptor antisense oligodeoxynucleotide intoseptum reduces vasopressin binding, social discrimination abilities, andanxiety-related behavior in rats.” Regul Pept 59(2): 229-39).

The V1a receptor is also mediating the cardiovascular effects ofvasopressin in the brain by centrally regulating blood pressure andheart rate in the solitary tract nucleus (Michelini, L. C. and M. Morris(1999). “Endogenous vasopressin modulates the cardiovascular responsesto exercise.” Ann NY Acad Sci 897: 198-211). In the periphery it inducesthe contraction of vascular smooth muscles and chronic inhibition of theV1a receptor improves hemodynamic parameters in myocardial infarctedrats (Van Kerckhoven, R., I. Lankhuizen, et al. (2002). “Chronicvasopressin V(1A) but not V(2) receptor antagonism prevents heartfailure in chronically infarcted rats.” Eur J Pharmacol 449(1-2):135-41).

Thus, vasopressin receptor antagonists are useful as therapeutics in theconditions of dysmenorrhea, hypertension, chronic heart failure,inappropriate secretion of vasopressin, liver cirrhosis, nephroticsyndrome, obsessive compulsive disorder, anxiety and depressivedisorders.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I)

wherein

R¹ is H,

-   -   C₁₋₆-alkyl substituted by CN, C₁₋₆-alkoxy, OH, halo, or        NR^(i)R^(ii),    -   C₂₋₆-alkyl,    -   aryl, 5 or 6 membered heteroaryl or sulfonylaryl each of which        is optionally substituted by one or more B,    -   —(CH₂)_(m)—R^(a) wherein R^(a) is:        -   CN,        -   OR^(i),        -   NR^(i)R^(ii), or        -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or            5 or 6 membered heteroaryl each of which is optionally            substituted by one or more B,    -   or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein        R^(b) is:        -   C₁₋₆-alkyl,        -   C₁₋₆-alkoxy,        -   C₃₋₆-cycloalkyl,        -   —(CH₂)_(m)—NR^(iii)R^(iv),        -   NR^(i)R^(ii), or        -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or            5 or 6 membered heteroaryl each of which is optionally            substituted by one or more B,            or R¹ and R³ together with the indole ring to which they are            attached form a 5 or 6 membered heterocycloalkyl which is            optionally substituted by ═O, C(O)O—C₁₋₆-alkyl or            C₁₋₆-alkyl;            there is one or more R², wherein each R² is the same or            different,            R² is one or more H, OH, halo, CN, nitro, C₁₋₆-alkoxy,            —O—CH₂—C₂₋₆-alkenyl, benzyloxy, C₁₋₆-haloalkoxy, or            C₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv) or            halo,    -   or two R² together with the indole ring to which they are        attached form an oxo or dioxo bridge;

R³ is H,

-   -   F,    -   —(CO)—R^(c), wherein R^(c) is:        -   C₁₋₆ alkyl,        -   —(CH₂)_(n)—NR^(i)R^(ii),        -   —(CH₂)_(n)—NR^(iii)R^(iv), or        -   5 or 6 membered heterocycloalkyl optionally substituted by            C₁₋₆-alkyl,    -   or C₁₋₆-alkyl which is optionally substituted by        -   halo,        -   NR^(i)R^(ii),        -   NR^(iii)R^(iv),        -   —O(CO)—C₁₋₆-alkyl, or        -   —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyl optionally            substituted by halo or nitro, or R^(d) is aryl or a 5 or 6            membered heteroaryl, each of which is optionally substituted            by halo, nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl;            A is selected from the group consisting of (a), (a′),            (b), (c) and (d):

whereinR⁴ is —NH(CO)R^(e), wherein R^(e) is

-   -   C₁₋₆-alkoxy or aryl each of which is optionally substituted by        halo,    -   C₁₋₆-alkoxy, or    -   CN,    -   oraryl, 5 or 6 membered heteroaryl, benzyl, aryloxy or a 9 or        10-membered bicyclic heteroaryl ring, each of which is        optionally substituted by CN, halo, C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₁₋₆-haloalkyl, nitro, hydroxyl, NR^(i)R^(ii), NR^(iii)R^(iv),        C₁₋₆-alkoxy-C₁₋₆-alkylene, S(O)₂—C₁₋₆-alkyl, or C₁₋₆-haloalkoxy,        or by an oxo or dioxo bridge;

R⁵ is H, OH, CN, COOR^(iii) or CONR^(iii)R^(iv);

R⁶ is C₂₋₆-alkyl,

-   -   —C(O)—R^(f) wherein R^(f) is an aryl group substituted by halo,        C₁₋₆-alkoxy, or CN, aryl, 5 or 6 membered heteroaryl, or a 9 or        10-membered bicyclic heteroaryl ring each of which is optionally        substituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl,        CN, nitro, NR^(i)R^(ii), NR^(iii)R^(iv),        C₁₋₆-alkoxy-C₁₋₆-alkylene, COOH, S(O)₂—C₁₋₆-alkyl, hydroxyl, or        C₁₋₆-haloalkoxy, or by an oxo or dioxo bridge,    -   or benzyl substituted by halo, C₁₋₆-alkyl, or C₁₋₆-haloalkyl or        by an oxo- or dioxo bridge;        B is halo,    -   CN,    -   NR^(i)R^(ii),    -   C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,    -   C₁₋₆-haloalkyl,    -   C₁₋₆-alkoxy,    -   C₁₋₆-haloalkoxy,    -   C₃₋₆-cycloalkyl,    -   —C(O)O—C₁₋₆-alkyl,    -   —C(O)NR^(i)R^(ii),    -   —C(O)—C₁₋₆-alkyl,    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂—NR^(i)R^(ii), or    -   (CR^(iii)R^(iv))_(n)-phenyl or (CR^(iii)R^(iv))_(n)-5 or 6        membered heteroaryl wherein the phenyl or 5 or 6 membered        heteroaryl moiety is optionally substituted by one or more        substituent(s) selected from the group consisting of:        -   halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionally substituted by            CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,            C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii),            —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and            —S(O)₂—NR^(i)R^(ii);            R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,            C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl,            —C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or            —S(O)₂—NR^(iii)R^(iv);            R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;            m is 1 to 6; and            n is 0 to 4;            and pharmaceutically acceptable salts thereof.

The compounds of formula (I) can contain asymmetric carbon atoms.Accordingly, the present invention includes all stereioisomeric forms ofthe compounds of formula I, including each of the individual enantiomersand mixtures thereof.

Compounds of formula (I) have good activity on the Via receptor.Therefore, the invention provides pharmaceutical compositions comprisinga therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof. The invention further providesa method fortreatiing dysmenorrhea, hypertension, chronic heart failure,inappropriate secretion of vasopressin, liver cirrhosis, nephroticsyndrome, obsessive compulsive disorder, anxiety and depressivedisorders by administering a compound of formula (I) or apharmaceutically acceptable salt thereof.

The preferred indications with regard to the present invention are thetreatment of anxiety and depressive disorders.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination. It must be noted that, as used in thespecification and the appended claims, the singular forms “a”, “an,” and“the” include plural forms unless the context clearly dictatesotherwise.

As used herein, the term “aryl” means a monovalent cyclic aromatichydrocarbon moiety consisting of a mono-, bi- or tricyclic aromaticring. Examples of aryl moieties include, but are not limited to,optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl,indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl,aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl,diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl,benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, as well as those specificallyillustrated by the examples herein below. Substituents for aryl include,but are not limited to, halogen, C₁₋₆-alkyl, and C₁₋₆-alkoxy. Preferredaryl are phenyl and naphthyl, and still more preferably phenyl.

The term “aryloxy” denotes a group wherein the aryl residue is asdefined hereinabove, which is attached via an oxygen atom. The preferredaryloxy group is phenyloxy, optionally substituted by halo, e.g. F, aswell as those specifically illustrated by the examples herein below.

The term “C₁₋₆-alkyl” denotes a saturated straight- or branched-chainhydrocarbon group containing from 1 to 6 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl aswell as those specifically illustrated by the examples herein below.Preferred C₁₋₆-alkyl groups are C₁₋₄-groups, i.e. with 1-4 carbon atoms.

The term “C₁₋₆-alkoxy” denotes a group wherein the alkyl residues are asdefined above, which is attached via an oxygen atom. PreferredC₁₋₆-alkoxy groups are methoxy and ethoxy as well as those specificallyillustrated by the examples herein below.

The term “C₂₋₆-alkenyl” denotes a carbon chain of 2 to 6 carbon atomscomprising a double bond in its chain. C₂₋₆-alkenyl groups includeethenyl, propen-1-yl, propen-2-yl, buten-1-yl, buten-3-yl, penten-1-yl,penten-2-yl, penten-3-yl, penten-4-yl, hexen-1-yl, hexen-2-yl,hexen-3-yl, hexen-4-yl and hexen-5-yl, as well as those specificallyillustrated by the examples herein below.

The term “benzyloxy” denotes a benzyl group attached via an oxygen atom.

The term “halogen” or “halo” denotes chlorine (Cl), iodine (I), fluorine(F) and bromine (Br).

The term “C₁₋₆-haloalkyl” denotes a C₁₋₆-alkyl group as defined abovewhich is substituted by one or more halogen atom. Examples ofC₁₋₆-haloalkyl include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexylsubstituted by one or more Cl, F, Br or I atom(s) as well as thosegroups specifically illustrated by the examples herein below. PreferredC₁₋₆-haloalkyl are difluoro- or trifluoro-methyl or ethyl.

“C₁₋₆-haloalkoxy” denotes a C₁₋₆-alkoxy group as defined above which issubstituted by one or more halogen atoms. Examples of C₁₋₆-haloalkoxyinclude, but are not limited to, methoxy or ethoxy, substituted by oneor more Cl, F, Br or I atom(s) as well as those groups specificallyillustrated by the examples herein below. Preferred C₁₋₆-haloalkoxy aredifluoro- or trifluoro-methoxy or ethoxy.

The term “C₃₋₆-cycloalkyl” denotes a monovalent or divalent saturatedcarbocyclic moiety consisting of a monocyclic ring. Cycloalkyl canoptionally be substituted with one, two, three or four substituents,wherein each substituent is independently hydroxy, C₁₋₆-alkyl,C₁₋₆-alkoxy, halogen, or amino, unless otherwise specifically indicated.Examples of cycloalkyl moieties include optionally substitutedcyclopropyl, optionally substituted cyclobutyl, optionally substitutedcyclopentyl and optionally substituted cyclohexyl as well as thosespecifically illustrated by the examples herein below.

The term “4 to 7 membered heterocycloalkyl” means a monovalent saturatedmoiety, consisting of one ring of 4 to 7 atoms as ring members,including one, two, or three heteroatoms chosen from nitrogen, oxygen orsulfur, the rest being carbon atoms. 4 to 7 membered heterocycloalkylcan optionally be substituted with one, two, three or four substituents,wherein each substituent is independently hydroxy, C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-thioalkyl, halo, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl,alkoxycarbonyl, amino, C₁₋₆-alkylamino, di(C₁₋₆)alkylamino,aminocarbonyl, or carbonylamino, unless otherwise specificallyindicated. Examples of heterocyclic moieties include, but are notlimited to, optionally substituted oxetane, optionally substitutedtetrahydro-furanyl, optionally substituted piperidinyl, optionallysubstituted pyrrolidinyl, optionally substituted morpholinyl, optionallysubstituted piperazinyl, and the like or those which are specificallyexemplified herein. Substituents can be selected from C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-haloalkyl, halo, CN, OH, and NH₂, as well as thosesubstituents which are specifically illustrated in the exampleshereinafter. Preferred 4 to 7 membered heterocycloalkyl are 5 to 6membered heterocycloalkyl.

The term “5 or 6 membered heteroaryl” means an aromatic ring of 5 or 6ring atoms as ring members containing one, two, or three ringheteroatoms selected from N, O, or S, the rest being carbon atoms. 5 or6 heteroaryl can optionally be substituted with one, two, three or foursubstituents, wherein each substituent is independently hydroxy,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-thioalkyl, halo, C₁₋₆-haloalkyl,C₁₋₆-hydroxyalkyl, alkoxycarbonyl, amino, C₁₋₆-alkylamino,di(C₁₋₆)alkylamino, aminocarbonyl, or carbonylamino, unless otherwisespecifically indicated. Examples of heteroaryl moieties include, but arenot limited to, optionally substituted imidazolyl, optionallysubstituted oxazolyl, optionally substituted thiazolyl, optionallysubstituted pyrazinyl, optionally substituted pyrrolyl, optionallysubstituted pyrazinyl, optionally substituted pyridinyl, optionallysubstituted pyrimidinyl, optionally substituted furanyl, and those whichare specifically exemplified herein.

The term “sulfonylaryl” denotes an aryl group as defined hereinabovewhich is attached via a sulfonyl group.

The term “9 or 10 membered bicyclic heteroaryl” means an aromaticbicyclic ring of 9 or 10 ring atoms as ring members containing one, two,or three ring heteroatoms selected from N, O, or S, the rest beingcarbon atoms. 9 or 10 membered bicyclic heteroaryl can optionally besubstituted with one, two, three or four substituents, wherein eachsubstituent is independently hydroxy, —C(O), C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-thioalkyl, halo, C₁₋₆-haloalkyl, C₁₋₆-hydroxyalkyl, alkoxycarbonyl,amino, C₁₋₆-alkylamino, di(C₁₋₆)alkylamino, aminocarbonyl, orcarbonylamino, unless otherwise specifically indicated. Examples of 9membered bicyclic heteroaryl moieties include, but are not limited to,optionally substituted indolyl, optionally substitutedthieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, benzoxazolyl,benzisoxazolyl as well as those 9 membered bicyclic heteroaryl which arespecifically exemplified herein.

The expression “two R² together with the indole ring to which they areattached form an oxo or dioxo bridge” denotes an oxo or dioxo bridge ofthe following formulae:

which bind two adjacent carbon atoms of the phenyl or indole ring of thecompound of formula (I) to which R² is binding.

Analogously, the expression “oxo or dioxo bridge” denotes an oxo ordioxo bridge of the following formulae:

Examples of group illustrating the expression “R¹ and R³ together withthe indole ring to which they are attached form a 5 or 6 memberedheterocycloalkyl which is optionally substituted by ═O” are:

as well as those specifically illustrated by the examples.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid, as well as thosespecifically illustrated by the examples herein below.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

The present invention provides compounds of formula (I)

wherein

R¹ is H,

-   -   C₁₋₆-alkyl substituted by CN, C₁₋₆-alkoxy, OH, halo, or        NR^(i)R^(ii),    -   C₂₋₆-alkyl,    -   aryl, 5 or 6 membered heteroaryl or sulfonylaryl each of which        is optionally substituted by one or more B,    -   —(CH₂)_(m)—R^(a) wherein R^(a) is:        -   CN,        -   OR^(i),        -   NR^(i)R^(ii), or        -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or            5 or 6 membered heteroaryl each of which is optionally            substituted by one or more B,    -   or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein        R^(b) is:        -   C₁₋₆-alkyl,        -   C₁₋₆-alkoxy,        -   C₃₋₆-cycloalkyl,        -   —(CH₂)_(m)—NR^(ii)R^(iv),        -   NR^(i)R^(ii), or        -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or            5 or 6 membered heteroaryl each of which is optionally            substituted by one or more B,            or R¹ and R³ together with the indole ring to which they are            attached form a 5 or 6 membered heterocycloalkyl which is            optionally substituted by ═O, C(O)O—C₁₋₆-alkyl or            C₁₋₆-alkyl;            there is one or more R², wherein each R² is the same or            different,            R² is one or more H, OH, halo, CN, nitro, C₁₋₆-alkoxy,            —O—CH₂—C₂₋₆-alkenyl, benzyloxy, C₁₋₆-haloalkoxy, or            C₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv) or            halo,    -   or two R² together with the indole ring to which they are        attached form an oxo or dioxo bridge;

R³ is H,

-   -   F,    -   —(CO)—R^(c), wherein R^(c) is:        -   C₁₋₆ alkyl,        -   —(CH₂)_(n)—NR^(i)R^(ii),        -   —(CH₂)_(n)—NR^(iii)R^(iv), or        -   5 or 6 membered heterocycloalkyl optionally substituted by            C₁₋₆-alkyl,    -   or C₁₋₆-alkyl which is optionally substituted by        -   halo,        -   NR^(i)R^(ii),        -   NR^(iii)R^(iv),        -   —O(CO)—C₁₋₆-alkyl, or        -   —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyl optionally            substituted by halo or nitro, or R^(d) is aryl or a 5 or 6            membered heteroaryl, each of which is optionally substituted            by halo, nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl;            A is selected from the group consisting of (a), (a′),            (b), (c) and (d):

whereinR⁴ is —NH(CO)R^(e), wherein R^(e) is

-   -   C₁₋₆-alkoxy or aryl each of which is optionally substituted by        halo,    -   C₁₋₆-alkoxy, or    -   CN,    -   oraryl, 5 or 6 membered heteroaryl, benzyl, aryloxy or a 9 or        10-membered bicyclic heteroaryl ring, each of which is        optionally substituted by CN, halo, C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₁₋₆-haloalkyl, nitro, hydroxyl, NR^(i)R^(ii), NR^(iii)R^(iv),        C₁₋₆-alkoxy-C₁₋₆-alkylene, S(O)₂—C₁₋₆-alkyl, or C₁₋₆-haloalkoxy,        or by an oxo or dioxo bridge;

R⁵ is H, OH, CN, COOR^(iii) or CONR^(iii)R^(iv);

R⁶ is C₂₋₆-alkyl,

-   -   —C(O)—R^(f) wherein R^(f) is an aryl group substituted by halo,        C₁₋₆-alkoxy, or CN, aryl, 5 or 6 membered heteroaryl, or a 9 or        10-membered bicyclic heteroaryl ring each of which is optionally        substituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl,        CN, nitro, NR^(i)R^(ii), NR^(iii)R^(iv),        C₁₋₆-alkoxy-C₁₋₆-alkylene, COOH, S(O)₂—C₁₋₆-alkyl, hydroxyl, or        C₁₋₆-haloalkoxy, or by an oxo or dioxo bridge,    -   or benzyl substituted by halo, C₁₋₆-alkyl, or C₁₋₆-haloalkyl or        by an oxo- or dioxo bridge;        B is halo,    -   CN,    -   NR^(i)R^(ii),    -   C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,    -   C₁₋₆-haloalkyl,    -   C₁₋₆-alkoxy,    -   C₁₋₆-haloalkoxy,    -   C₃₋₆-cycloalkyl,    -   —C(O)O—C₁₋₆-alkyl,    -   —C(O)NR^(i)R^(ii),    -   —C(O)—C₁₋₆-alkyl,    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂—NR^(i)R^(ii), or    -   (CR^(iii)R^(iv))_(n)-phenyl or (CR^(iii)R^(iv))_(n)-5 or 6        membered heteroaryl wherein the phenyl or 5 or 6 membered        heteroaryl moiety is optionally substituted by one or more        substituent(s) selected from the group consisting of:        -   halo, CN, C₁₋₆-alkyl optionally substituted by CN or            C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl,            —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii), —C(O)—C₁₋₆-alkyl,            —S(O)₂—C₁₋₆-alkyl, and —S(O)₂—NR^(i)R^(ii);            R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,            C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl,            —C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or            —S(O)₂—NR^(iii)R^(iv);            R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;            m is 1 to 6; and            n is 0 to 4;            and pharmaceutically acceptable salts thereof.

In certain embodiments of the invention, the compounds of formula (I)are those compounds wherein:

R¹ is H,

-   -   C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,    -   aryl, 5 or 6 membered heteroaryl or sulfonylaryl each of which        is optionally substituted by one or more B,    -   —(CH₂)_(m)—R^(a) wherein R^(a) is:        -   CN,        -   OR^(i),        -   NR^(i)R^(ii), or        -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or            5 or 6 membered heteroaryl each of which is optionally            substituted by one or more B,    -   or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein        R^(b) is:        -   C₁₋₆-alkyl,        -   C₁₋₆-alkoxy,        -   C₃₋₆-cycloalkyl,        -   —(CH₂)_(m)—NR^(ii)R^(iv),        -   NR^(i)R^(ii), or        -   C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or            5 or 6 membered heteroaryl each of which is optionally            substituted by one or more B,            or R¹ and R³ together with the indole ring to which they are            attached form a 5 or 6 membered heterocycloalkyl which is            optionally substituted by (CO);            there is one or more R², wherein each R² is the same or            different,            R² is one or more H, OH, halo, CN, nitro, C₁₋₆-alkyl            optionally substituted by —NR^(iii)R^(iv), C₁₋₆-alkoxy,            —O—CH₂—C₂₋₆-alkenyl, or benzyloxy,    -   or two R² together with the indole ring to which they are        attached form an oxo or dioxo bridge;

R³ is H,

-   -   halo,    -   —(CO)—R^(c), wherein R^(c) is:        -   C₁₋₆-alkyl,        -   —(CH₂)_(n)—NR^(i)R^(ii),        -   —(CH₂)_(n)—NR^(iii)R^(iv), or        -   5 or 6 membered heterocycloalkyl optionally substituted by            C₁₋₆-alkyl,    -   or C₁₋₆-alkyl or aryl, each of which is optionally substituted        by        -   halo,        -   —O(CO)—C₁₋₆-alkyl, or        -   —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyl optionally            substituted by halo or nitro, or R^(d) is aryl or a 5 or 6            membered heteroaryl, each of which is optionally substituted            by halo, nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl;            A is selected from the group consisting of (a), (b), (c) and            (d):

whereinR⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy or aryl optionallysubstituted by halo,

-   -   C₁₋₆-alkoxy, or    -   CN,    -   or aryl, 5 or 6 membered heteroaryl, benzyl, aryloxy or a 9 or        10-membered bicyclic heteroaryl ring each of which is optionally        substituted by CN, halo, C₁₋₆-alkyl, C₁₋₆-alkoxy, or        C₁₋₆-haloalkyl, or by a dioxo bridge;

R⁵ is H, OH, CN, COOR^(iii) or CONR^(iii)R^(iv);

R⁶ is C₁₋₆-alkyl,

-   -   —C(O)—R^(f) wherein R^(f) is an aryl group optionally        substituted by halo, C₁₋₆-alkoxy, or CN,    -   or aryl, 5 or 6 membered heteroaryl, benzyl, or a 9 or        10-membered bicyclic heteroaryl ring each of which is optionally        substituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl, or        CN or by a dioxo bridge;        B is halo,    -   CN,    -   NR^(i)R^(ii),    -   C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,    -   C₁₋₆-alkoxy,    -   C₁₋₆-haloalkoxy,    -   C₃₋₆-cycloalkyl,    -   —C(O)O—C₁₋₆-alkyl,    -   —C(O)NR^(i)R^(ii),    -   —C(O)—C₁₋₆-alkyl,    -   —S(O)₂—C₁₋₆-alkyl,    -   —S(O)₂—NR^(i)R^(ii),    -   (CR^(iii)R^(iv))_(n)-phenyl, or (CR^(iii)R^(iv))_(n)-5 or 6        membered heteroaryl wherein the phenyl or 5 or 6 membered        heteroaryl moiety is optionally substituted by one or more        substituent(s) selected from the group consisting of:        -   halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionally substituted by            CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,            C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii),            —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and            —S(O)₂—NR^(i)R^(ii);            R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,            C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl,            —C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or            —S(O)₂—NR^(iii)R^(iv);            R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;            m is 1 to 6; and            n is 0 to 4;            and pharmaceutically acceptable salts thereof.

In certain embodiments of the invention, the compounds of formula (I)are those compounds wherein:

R¹ is H,

-   -   C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,    -   aryl,    -   5 or 6 membered heteroaryl,    -   sulfonylaryl,    -   —(CH₂)_(m)—R^(a) wherein R^(a) is C₃₋₆-cycloalkyl, 5 or 6        membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl        each of which is optionally substituted by one or more        substituents selected from the group consisting of:        -   halo, CN, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,            —C(O)O—C₁₋₆-alkyl and phenyl optionally substituted by halo,            C₁₋₆-alkyl, C₁₋₆-haloalkyl or C₁₋₆-alkoxy,    -   —(CH₂)_(m)—NR^(i)R^(ii),    -   or —(CH₂)_(n)—(CO)—R^(b), wherein R^(b) is aryl or 5 or 6        membered-heterocycloalkyl; there is one or more R², wherein each        R² is the same or different,        R² is one or more H, halo, CN, nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy,        —O—CH₂—C₂₋₆-alkenyl, or benzyloxy, or two R² together with the        indole ring to which they are attached form an oxo or dioxo        bridge;

R³ is H,

-   -   halo,    -   —(CO)—R^(c), wherein R^(c) is C₁₋₆-alkyl, 5 or 6 membered        heterocycloalkyl optionally substituted by C₁₋₆-alkyl, or R^(c)        is —(CH₂)_(n)—NR^(i)R^(ii),    -   or C₁₋₆-alkyl or aryl, each of which is optionally substituted        by        -   —O(CO)—C₁₋₆-alkyl or —NH(CO)R^(d), wherein R^(d) is            C₁₋₆-alkyl optionally substituted by halo or nitro, or R^(d)            is aryl or a 5 or 6 membered heteroaryl, each of which is            optionally substituted by halo, nitro, C₁₋₆-alkyl or            C₁₋₆-haloalkyl;            R^(i) and R^(ii) are each independently selected from H,            C₁₋₆-alkyl and —(CO)O—C₁₋₆-alkyl;            m is 1 to 6; and            n is 0 to 4;            A is selected from the group consisting of (a), (b), (c) and            (d):

whereinR⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy, or aryl optionallysubstituted by halo,

-   -   or is aryl, benzyl, aryloxy or a 9 or 10-membered bicyclic        heteroaryl ring each of which is optionally substituted by halo,        C₁₋₆-alkyl, C₁₋₆-alkoxy, or C₁₋₆-haloalkyl, or by a dioxo        bridge;

R⁵ is H, OH or CN;

R⁶ is C₁₋₆-alkyl,

-   -   —C(O)—R^(f) wherein R^(f) is an aryl group optionally        substituted by halo,    -   or aryl, benzyl, or a 9 or 10-membered bicyclic heteroaryl ring        each of which is optionally substituted by halo, C₁₋₆-alkyl,        C₁₋₆-alkoxy, or C₁₋₆-haloalkyl, or by a dioxo bridge;        and pharmaceutically acceptable salts thereof.

In certain embodiments of the invention, the compounds of formula (I)are those compounds wherein:

R¹ is H,

-   -   C₁₋₆-alkyl substituted by NR^(i)R^(ii),    -   —(CH₂)_(m)—R^(a) wherein R^(a) is:        -   NR^(i)R^(ii), or        -   5 to 6 membered-heterocycloalkyl, aryl, or 5 or 6 membered            heteroaryl each of which is optionally substituted by one or            more B,    -   or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein        R^(b) is:        -   C₁₋₆-alkyl,        -   C₁₋₆-alkoxy,        -   NR^(i)R^(ii), or        -   5 to 6 membered-heterocycloalkyl, aryl, or 5 or 6 membered            heteroaryl which are optionally substituted by one or more            B,            or R¹ and R³ together with the indole ring to which they are            attached form a 5 or 6 membered heterocycloalkyl which is            optionally substituted by ═O, C(O)O—C₁₋₆-alkyl or            C₁₋₆-alkyl;            there is one or more R², wherein each R² is the same or            different,            R² is one or more H, halo, or C₁₋₆-alkyl;            R³ is H or C₁₋₆-alkyl;            A is selected from the group consisting of (a), (a′),            (b), (c) and (d):

whereinR⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy, or aryl optionallysubstituted by halo,

-   -   or is aryl, 5 or 6 membered heteroaryl, benzyl, aryloxy or a 9        or 10-membered bicyclic heteroaryl ring, each of which is        optionally substituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy,        C₁₋₆-haloalkyl, nitro, hydroxyl, or C₁₋₆-haloalkoxy, or by an        oxo or dioxo bridge; and

R⁵ is H, OH, or CN;

R⁶ is aryl, 5 or 6 membered heteroaryl, or a 9 or 10-membered bicyclicheteroaryl ring each of which is optionally substituted by halo,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl, CN, nitro, NR^(i)R^(ii),NR^(iii)R^(iv), C₁₋₆-alkoxy-C₁₋₆-alkylene, COOH, or S(O)₂—C₁₋₆-alkyl, orby an oxo or dioxo bridge;B is halo, C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,or C₁₋₆-alkoxy; R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl or —S(O)₂—C₁₋₆-alkyl;R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;m is 1 to 6; andn is 0 to 4;and pharmaceutically acceptable salts thereof.

Preferably, the invention encompasses compounds according to the generalformula (I) as described herein, with the proviso that R¹, R² and R³ arenot simultaneously H, as well as pharmaceutical acceptable saltsthereof.

Preferably, the invention encompasses compounds according to the generalformula (I) as described herein, with the proviso that R⁴ is not a1H-benzimidazole derivative:

optionally substituted by CN, halo, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkyl, nitro, hydroxyl, NR^(i)R^(ii), NR^(iii)R^(iv),C₁₋₆-alkoxy-C₁₋₆-alkylene, S(O)₂—C₁₋₆-alkyl, or C₁₋₆-haloalkoxy, or byan oxo or dioxo bridge.

Also encompassed by the compounds of formula (I) are the followingcompounds of formula (I-a) or (1-a′) according to the invention:

wherein R¹ to R⁴ are as defined hereinabove for formula (I).

Preferred compounds of formula (I-a) are those compounds wherein,

R¹ is H or —(CH₂)_(m)—R^(a) wherein R^(a) is aryl and m is 1 to 6;there is one or more R², wherein each R² is the same or different,R² is one or more H or halo;R³ is H or C₁₋₆-alkyl;R⁴ is aryl which is optionally substituted by halo or C₁₋₆-alkoxy;and pharmaceutically acceptable salts thereof.

Again, it is preferred that R¹, R² and R³ are not simultaneously H.

Examples of compounds according to the invention are:

-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;    and-   Benzyl-2-methyl-1H-indol-3-yl)-(3-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone.

Also encompassed by the compounds of formula (I) are the followingcompounds of formula (I-b) according to the invention:

wherein R¹ to R⁵ are as defined hereinabove for formula (I).

Preferred compounds of formula (I-b) are those compounds wherein,

R¹ is H,

-   -   —(CH₂)_(m)—R^(a) wherein R^(a) is:        -   NR^(i)R^(ii), or        -   aryl, or 5 or 6 membered heteroaryl each of which is            optionally substituted by one or more halo, C₁₋₆-alkyl,            C₁₋₆-alkoxy,    -   or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein        R^(b) is:        -   C₁₋₆-alkyl,        -   C₁₋₆-alkoxy,        -   NR^(i)R^(ii), or        -   5 to 6 membered-heterocycloalkyl, or 5 or 6 membered            heteroaryl each of which is optionally substituted by one or            more halo, C₁₋₆-alkyl, or C₁₋₆-alkoxy,            or R¹ and R³ together with the indole ring to which they are            attached form a 5 or 6 membered heterocycloalkyl which is            optionally substituted by C(O)O—C₁₋₆-alkyl or C₁₋₆-alkyl;            there is one or more R², wherein each R² is the same or            different,            R² is one or more H, halo or C₁₋₆-alkyl;            R³ is H or C₁₋₆-alkyl;            R⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy or aryl            which is optionally substituted by halo, or is aryl, benzyl,            aryloxy or a 9 or 10-membered bicyclic heteroaryl ring each            of which is optionally substituted by halo, C₁₋₆-alkyl,            C₁₋₆-alkoxy, C₁₋₆-haloalkyl, nitro, hydroxyl, or            C₁₋₆-haloalkoxy or by an oxo or dioxo bridge; and

R⁵ is H, OH or CN;

R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl, orC₁₋₆-alkyl-NR^(iii)R^(iv);R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;m is 1 to 6; andn is 0 to 4;and pharmaceutically acceptable salts thereof.

Again, it is preferred that R¹, R² and R³ are not simultaneously H.

Moreover, it is preferred that R⁴ is not an 1H-benzimidazole derivativeas described hereinabove.

Examples of compounds of formula (I-b) according to the invention are:

-   (4-Benzyl-4-hydroxy-piperidin-1-yl)-(1-benzyl-2-methyl-1H-indol-3-yl)-methanone;-   (4-Benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-chloro-benzyl)-2-methyl-1H-indol-3-yl]-methanone;-   Benzyl-5-chloro-2-methyl-1H-indol-3-yl)-(4-benzyl-4-hydroxy-piperidin-1-yl)-methanone;-   (4-Benzyl-4-hydroxy-piperidin-1-yl)-[5-chloro-1-(3-methoxy-benzyl)-2-methyl-1H-indol-3-yl]-methanone;-   (4-Benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-methoxy-benzyl)-2-methyl-1H-indol-3-yl]-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-methanone;-   Benzyl-2-methyl-1-indol-3-yl)-(4-hydroxy-4-phenyl-piperidin-1-yl)-methanone;-   Benzyl-2-methyl-1-indol-3-yl)-[4-(4-fluoro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone;-   Benzyl-2-methyl-1-indol-3-yl)-[4-(4-chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methanone;-   (4-Benzo[1,3]dioxol-5-yl-4-hydroxy-piperidin-1-yl)-(1-benzyl-2-methyl-1H-indol-3-yl)-methanone;-   Benzyl-2-methyl-1-indol-3-yl)-(4-hydroxy-4-p-tolyl-piperidin-1-yl)-methanone;-   Benzyl-2-methyl-1-indol-3-yl)-[4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone;-   1-(6-Chloro-1H-indole-3-carbonyl)-4-phenyl-piperidine-4-carbonitrile;-   (6-Chloro-1H-indol-3-yl)-(4-hydroxy-4-p-tolyl-piperidin-1-yl)-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methanone;-   [4-(4-Bromo-phenyl)-4-hydroxy-piperidin-1-yl]-(6-chloro-1H-indol-3-yl)-methanone;-   [1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-carbamic acid    tert-butyl ester;-   N-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-2-fluoro-benzamide;-   (6-Chloro-1H-indol-3-yl)-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-nitro-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-(4-methoxy-4-phenyl-piperidin-1-yl)-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone;-   N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;-   (6-Chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;-   N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide    or hydrochloride salt thereof;-   N-(2-Amino-ethyl)-2-[6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl]-acetamide    or hydrochloride salt thereof;-   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   [1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone;-   [1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone;-   [1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone;-   [1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide;-   (6-Chloro-1H-indol-3-yl)-(3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-yl)-methanone;-   (6-Chloro-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1-methanesulfonyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone;-   10-[4-(2-Methoxy-phenyl)-piperidine-1-carbonyl]-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylic    acid tert-butyl ester;-   [4-(2-Methoxy-phenyl)-piperidin-1-yl]-(1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanone    or hydrochloride salt thereof; and-   [4-(2-Methoxy-phenyl)-piperidin-1-yl]-(2-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanone.

Preferred examples of compounds of formula (I-b) according to theinvention are:

-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-bromo-phenyl)-4-hydroxy-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-(4-phenyl-piperidin-1-yl)-methanone;-   (4-Benzo[1,3]dioxol-5-yl-4-hydroxy-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(3-chloro-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-hydroxy-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-methanone;-   2-{3-[4-(2,6-Dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone;-   2-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-5-methyl-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone;-   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone    or hydrochloride salt thereof;-   [6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide    or hydrochloride salt thereof;-   N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide    or hydrochloride salt thereof;-   2-{6-Chloro-3-[4-(5-fluoro-benzo[d]    isoxazol-3-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-4-hydroxy-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;    and-   2-[6-Chloro-3-(3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carbonyl)-indol-1-yl]-N-methyl-acetamide.

Particularly preferred examples of compounds of formula (I-b) accordingto the invention are:

-   Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-piperidin-1-yl)-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-pyridin-2-yl-ethanone;-   (6-Chloro-1-pyridin-4-ylmethyl-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1-pyridin-3-ylmethyl-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   (6-Chloro-1-pyridin-2-ylmethyl-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   [6-Chloro-1-(6-chloro-pyridin-3-ylmethyl)-1H-indol-3-yl]-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   {6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic    acid tert-butyl ester;-   (6-Chloro-1-pyrazin-2-ylmethyl-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   [6-Chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   [6-Chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   {6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic    acid tert-butyl ester;-   2-{6-Chloro-3-[4-cyano-4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-cyano-4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{3-[4-(2,6-Dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   [6-Chloro-1-(2-methyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-isopropoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2-isopropoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone;-   2-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{5,6-Dichloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide;-   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   [6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone;-   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone    or hydrochloride salt thereof; and-   2-[6-Chloro-3-(3,4,5,6-tetrahydro-2H-[4,4]bipyridinyl-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide.

Also encompassed by the compounds of formula (I) are the followingcompounds of formula (I-c) according to the invention:

wherein R¹ to R³ and R⁶ are as defined hereinabove for formula (I).

Preferred compounds of formula (I-c) are those compounds wherein,

R¹ is H or

-   -   or is C₁₋₆-alkyl substituted by NR^(i)R^(ii),    -   or is —(CH₂)_(m)—R^(a) wherein R^(a) is:        -   NR^(i)R^(ii),        -   5 to 6 membered-heterocycloalkyl, aryl, or 5 or 6 membered            heteroaryl which are optionally substituted by one or more            C₁₋₆-alkyl,    -   or is —(CH₂)_(n)—(CO)—R^(b), wherein R^(b) is:        -   NR^(i)R^(ii),        -   5 to 7 membered-heterocycloalkyl which is optionally            substituted by one or more C_(1m)-alkyl;            R² is one or more of H, halo or C₁₋₆-alkyl;            R³ is H or C₁₋₆-alkyl;            R⁶ is aryl, 5 or 6 membered heteroaryl, or a 9 or            10-membered bicyclic heteroaryl ring which are optionally            substituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy,            C₁₋₆-haloalkyl, CN, nitro, NR^(i)R^(ii), NR^(iii)R^(iv),            C₁₋₆-alkoxy-C₁₋₆-alkylene, COOH, S(O)₂—C₁₋₆-alkyl, or by an            oxo or dioxo bridge;            R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,            C₁₋₆-alkyl-NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl, or            —S(O)₂—C₁₋₆-alkyl;            R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl;            m is 1 to 6; and            n is 0 to 4;            and pharmaceutically acceptable salts thereof.

It is preferred that R¹, R² and R³ are not simultaneously H.

Examples of compounds of formula (I-c) according to the invention are:

-   Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-piperazin-1-yl)-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-phenyl)-piperazin-1-yl]-methanone;-   Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-chloro-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-(4-phenyl-piperazin-1-yl)-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2,6-dichloro-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-nitro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-chloro-phenyl)-piperazin-1-yl]-methanone;-   [4-(2-Amino-6-chloro-phenyl)-piperazin-1-yl]-(6-chloro-1H-indol-3-yl)-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(3-methoxy-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-nitro-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(3-fluoro-phenyl)-piperazin-1-yl]-methanone;-   3-Chloro-4-[4-(6-chloro-1H-indole-3-carbonyl)-piperazin-1-yl]-benzonitrile;-   (6-Chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-5-methyl-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone    or hydrochloride salt thereof;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide    or hydrochloride salt thereof;-   N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide    or hydrochloride salt thereof;-   [1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;-   [6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;-   [6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;-   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   [1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;-   N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2-methoxymethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;-   2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamide;-   (6-Chloro-1H-indol-3-yl)-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(3-methyl-pyridin-2-yl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(3,5-dichloro-pyridin-4-yl)-piperazin-1-yl]-methanone;-   (6-Chloro-1H-indol-3-yl)-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone;-   2-[4-(6-Chloro-1H-indole-3-carbonyl)-piperazin-1-yl]-nicotinonitrile;-   (6-Chloro-1H-indol-3-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone;-   (6-Chloro-1H-indol-3-yl)-(4-thiazol-2-yl-piperazin-1-yl)-methanone;-   2-[6-Chloro-3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carbonyl)-indol-1-yl]-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(3-methyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(3,5-dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;-   2-[6-Chloro-3-(4-thiazol-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(3-cyano-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   (6-Chloro-1-(S)-1-piperidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1-(RS)-1-pyrrolidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   [6-Chloro-1-((S)-1-methyl-piperidin-3-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   [6-Chloro-1-((RS)-1-methyl-pyrrolidin-3-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   2-[6-Chloro-3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(3-methyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(3,5-dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;-   2-[6-Chloro-3-(4-thiazol-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(3-cyano-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-[6-Chloro-3-(4-pyrimidin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;-   (6-Chloro-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(6-chloro-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-[6-Chloro-3-(4-thieno[2,3-c]pyridin-7-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-[4-(6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carbonyl)-piperazin-1-yl]-nicotinic    acid;-   2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;    and-   2-{6-Chloro-3-[4-(4-fluoro-2-methanesulfonyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide.

Preferred examples of compounds of formula (I-c) according to theinvention are:

-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;-   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone;-   2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   2-{6-Chloro-3-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;-   [1-((S)-2-Amino-propyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   (6-Chloro-1-(S)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   [6-Chloro-1-((S)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   2-{6-Chloro-3-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;-   (6-Chloro-1-(R)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   [6-Chloro-1-((R)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;-   N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-acetamide;-   N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-methanesulfonamide;-   N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-N-methyl-acetamide;-   N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-N-methyl-methanesulfonamide;-   2-[6-Chloro-3-(4-thieno[3,2-c]pyridin-4-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;    and-   2-{6-Chloro-3-[4-(3-iodo-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide.

Also encompassed by the compounds of formula (I) are the followingcompounds of formula (I-d) according to the invention:

wherein R¹ to R³ and R⁶ are as defined hereinabove for formula (I).

Again, it is preferred that R¹, R² and R³ are not simultaneously H.

Preferred compounds of formula (I-d) are those compounds wherein thesubstitution pattern is analogous to that of the preferred compounds offormula (I-c), and further preferred are those compounds wherein

R¹ is H;

R² is one or more halo;

R³ is H;

R⁶ is aryl substituted by C₁₋₆-alkoxy;and pharmaceutically acceptable salts thereof.

As an example,(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-4-oxy-piperazin-1-yl]-methanoneis mentioned.

The combinations of the substitution patterns provided herein forcompounds of formula (I), (I-a), (I-a′), (I-b), (I-c) and (I-d) for eachof the embodiments provided are also encompassed by the invention.

The invention also encompasses methods for the treatment ofdysmenorrhea, hypertension, chronic heart failure, inappropriatesecretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessivecompulsive disorder, anxiety or depressive disorders which compriseadministering a compound of formulae (I), (I-a), (I-a′), (I-b), (I-c) or(I-d).

The invention also encompasses a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I), (I-a),(I-a′), (I-b), (I-c) or (I-d) and a pharmaceutically acceptable carrier.Such pharmaceutical compositions are useful for treating dysmenorrhea,hypertension, chronic heart failure, inappropriate secretion ofvasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsivedisorder, anxiety and depressive disorders.

In a certain embodiment, the compounds of formula (I) of the inventioncan be manufactured according to a process comprising reacting acompound of formula (II):

with a compound of formula A-H, to obtain a compound of formula (I)wherein A, R¹, R² and R³ are as defined hereinabove for formula (I).

In another embodiment, the compounds of formula (I) of the invention canbe manufactured according to a process comprising reacting a compound offormula (I-1), wherein R¹ is H:

with a compound of formula R¹—X, to obtain a compound of formula (I)wherein A, R¹, R² and R³ are as defined hereinabove for formula (I) andX is halo.

In another embodiment, the compounds of formula (I) of the invention canbe manufactured according to a process comprising hydrolyzing a compoundof formula (V):

to obtain a compound of formula (II):

and then reacting the compound of formula (II) with a compound offormula A-H, to obtain a compound of formula (I) wherein R¹, R² and R³are as defined hereinabove for formula (I).

These processes are described more in details with the following generalschemes and procedures A to C.

General Scheme A

Compounds of formula (I) can be prepared via an amide coupling betweenan indole 3-carboxylic acid (II) and a compound of formula (A-H),wherein A is defined as hereinabove. The usual reagents and protocolsknown in the art can be used to effect the amide coupling. Indole3-carboxylic acids (II) are either commercially available or readilyprepared using a procedure described in J. Med. Chem. 1991, 34, 140.Alternatively, they can be prepared following the general scheme C asdescribed hereinafter. The compounds of formula (A-H) are eithercommercially available or prepared using methods known in the artstarting from commercially available materials. General scheme A ishereinafter further illustrated with general procedure I.

General Procedure B

Compounds of formula (I) with R¹ different from H can be prepared usingmethods known in the art, e.g. by N-deprotonation of a compound offormula (I-1) (compounds of formula (I) wherein R¹ is H) followed bytreatment with an electrophilic reactant R¹—X (wherein X is a leavinggroup, e.g. halo) which is either commercially available or easilyprepared according to methods well known in the art and commerciallyavailable starting materials. General scheme B is hereinafter furtherillustrated with general procedure II.

General Procedure C

The treatment of an indole derivative (III-1) with trifluoroaceticanhydride in DMF affords intermediate (IV) which can be hydrolyzed withan aqueous sodium hydroxide solution to give the 3-carboxylic acidindole derivative (II-1). Alternatively, (IV) could react with anelectrophilic reactant R¹—X to give (V), which is then converted to thecorresponding carboxylic acid derivative (II) with NaH/H₂O in DMF (seeJ. Org. Chem., 1993, 10, 2862). Intermediate (V) can alternatively beobtained by treatment of an indole derivative (III-2) withtrifluoroacetic anhydride in a suitable solvent, e.g. DMF,dichloromethane or 1,2-dichloroethane. Addition of a suitable base maybe advantageous.

V1a Activity Material & Method:

The human V1a receptor was cloned by RT-PCR from total human liver RNA.The coding sequence was subcloned in an expression vector aftersequencing to confirm the identity of the amplified sequence. Todemonstrate the affinity of the compounds from the present invention tothe human V1a receptor binding studies were performed. Cell membraneswere prepared from HEK293 cells transiently transfected with theexpression vector and grown in 20 liter fermenters with the followingprotocol.

50 g of cells are resuspended in 30 ml freshly prepared ice cold Lysisbuffer (50 mM HEPES, 1 mM EDTA, 10 mM MgCl2 adjusted to pH=7.4+completecocktail of protease inhibitor (Roche Diagnostics)). Homogenized withPolytron for 1 min and sonicated on ice for 2×2 minutes at 80% intensity(Vibracell sonicator). The preparation is centrifuged 20 min at 500 g at4° C., the pellet is discarded and the supernatant centrifuged 1 hour at43,000 g at 4° C. (19′000 rpm). The pellet is resuspended in 12.5 mlLysis buffer+12.5 ml Sucrose 20% and homogenized using a Polytron for1-2 min. The protein concentration is determined by the Bradford method,and aliquots are stored at −80° C. until use. For binding studies 60 mgYttrium silicate SPA beads (Amersham) are mixed with an aliquot ofmembrane in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mMCaCl₂, 10 mM MgCl₂) for 15 minutes with mixing. 50 ul of bead/membranemixture is then added to each well of a 96 well plate, followed by 50 ulof 4 nM 3H-Vasopressin (American Radiolabeled Chemicals). For totalbinding measurement 100 ul of binding buffer are added to the respectivewells, for non-specific binding 100 ul of 8.4 mM cold vasopressin andfor compound testing 100 ul of a serial dilution of each compound in 2%DMSO. The plate is incubated 1 h at room temperature, centrifuged 1 minat 1000 g and counted on a Packard Top-Count. Non-specific bindingcounts are subtracted from each well, and data is normalized to themaximum specific binding set at 100%. To calculate an IC 50 the curve isfitted using a non-linear regression model (XLfit) and the Ki iscalculated using the Cheng-Prussoff equation.

Ex. No. Ki (nM) 3 14 24 10 40 8 43 2 44 3 45 7 46 7 47 4 48 7 49 3 50 451 0 52 4 55 2 56 2 57 2 58 9 59 2 60 8 61 13 62 11 63 2 66 4 67 5 69 671 5 72 3 76 8 80 6 81 13 82 2 84 11 87 4 88 7 90 8 95 13 96 11 97 6 1027 106 5 107 12 108 8 111 7 114 3 115 11 117 6 118 12 122 10 151 14 15214 153 23 162 27 163 22 171 7 172 10 174 3 175 32 176 8 177 8 190 19 19626 198 20 200 21 203 2 205 10 211 13 214 16 215 6 217 21 218 16 219 15220 17 224 27 225 12

The present invention also provides pharmaceutical compositionscontaining compounds of the invention or pharmaceutically acceptablesalts thereof and a pharmaceutically acceptable carrier. Suchpharmaceutical compositions can be in the form of tablets, coatedtablets, dragées, hard and soft gelatin capsules, solutions, emulsionsor suspensions. The pharmaceutical compositions also can be in the formof suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic excipients for theproduction of tablets, coated tablets, dragées, and hard gelatincapsules. Lactose, corn starch or derivatives thereof, talc, stearicacid or its salts etc can be used as such excipients e.g. for tablets,dragées and hard gelatin capsules. Suitable excipients for soft gelatincapsules are e.g. vegetable oils, waxes, fats, semi-solid and liquidpolyols etc. Suitable excipients for the manufacture of solutions andsyrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.Suitable excipients for injection solutions are e.g. water, alcohols,polyols, glycerol, vegetable oils etc. Suitable excipients forsuppositories are e.g. natural or hardened oils, waxes, fats,semi-liquid or liquid polyols etc.

Moreover, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The present invention also provides a method for the manufacture ofpharmaceutical compositions. Such process comprises bringing one or morecompounds of formula I and/or pharmaceutically acceptable acid additionsalts thereof and, if desired, one or more other therapeuticallyvaluable substances into a galenical administration form together withone or more therapeutically inert carriers.

Compounds of formula (I) have good activity on the V1a receptor. Theinvention provides methods for treating dysmenorrhea, hypertension,chronic heart failure, inappropriate secretion of vasopressin, livercirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxietyand depressive disorders by administering a compound of formula (I) or apharmaceutically acceptable salt thereof. The preferred indications withregard to the present invention are the treatment of anxiety anddepressive disorders.

The compounds and compositions of the invention can be administered in aconventional manner, for example, orally rectally, or parenterally. Thepharmaceutical compositions of the invention can be administered orally,for example, in the form of tablets, coated tablets, dragees, hard andsoft gelatin capsules, solutions, emulsions, or suspensions. Thepharmaceutical compositions also can be administered rectally, forexample, in the form of suppositories, or parenterally, for example, inthe form of injectable solutions.

The dosage at which a compound of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, in the case of oraladministration a daily dosage of about 10 to 1000 mg per person of acompound of general formula (I), (I-a), (I-b); (I-c) or (I-d) should beappropriate, although the above upper limit can also be exceeded whennecessary.

The following Examples illustrate the present invention without limitingit. All temperatures are given in degrees Celsius.

Example A

Tablets of the following composition are manufactured in the usualmanner:

mg/tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystallinecellulose 34 Magnesium stearate 1 Tablet weight 100

Example B

Capsules of the following composition are manufactured:

mg/capsule Active substance 10 Lactose 155 Corn starch 30 Talc 5 Capsulefill weight 200

The active substance, lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer, the talc is added thereto and mixed thoroughly. The mixture isfilled by machine into hard gelatin capsules.

Example C

Suppositories of the following composition are manufactured:

mg/supp. Active substance 15 Suppository mass 1285 Total 1300

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C.

Thereupon, the finely powdered active substance is added thereto andstirred until it has dispersed completely. The mixture is poured intosuppository moulds of suitable size, left to cool; the suppositories arethen removed from the moulds and packed individually in wax paper ormetal foil.

Where journal references are cited in the examples, the example wasperformed using the starting material listed with the reactants andconditions cited in the reference. All procedures in such references arewell known to those of ordinary skill in the art. All journal referencescited herein are incorporated by reference.

EXAMPLES General Procedure I Amide Coupling

To a stirred solution of an indole-3-carboxylic acid derivative (1 mmol)in 10 ml CH₂Cl₂ were added (1.3 mmol) EDC, (1.3 mmol) HOBt, (1.3 mmol)Et₃N and (1 mmol) of the amine derivative. The mixture was stirredovernight at RT and then poured onto water and extracted with CH₂Cl₂.The combined organic phases were dried over Na₂SO₄ and concentrated invacuo. Flash chromatography or preparative HPLC afforded the titlecompound.

General procedure II Alkylation

To a stirred solution of(6-chloro-1H-indol-3-yl)-(4-phenyl-piperidin-1-yl)-methanone in DMF wereadded 2.1 eq. NaH (60% in oil). The mixture was stirred at RT for 30min. and then the electrophilic reagent R¹—X (1.1 eq.) was added. Themixture was stirred an additional 14 hours at 60° C. and then pouredonto water and extracted with ethyl acetate. The combined organic phaseswere dried over Na₂SO₄ and concentrated in vacuo. Purification bypreparative HPLC afforded the corresponding derivatives.

Acid Intermediates of Formula II and II-1 Acid 16-Chloro-1H-indole-3-carboxylic acid

Using a procedure described in J. Med. Chem. 1991, 34, 140, from 7.0 g(0.046 mmol) of 6-chloro-1H-indole were prepared 5.80 g (64%) of6-chloro-1H-indole-3-carboxylic acid as a light brown solid.

ES-MS m/e (%): 194 (M−H⁺).

Acid 2 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid1-(6-Chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

Using a procedure described in J. Med. Chem. 1991, 34, 140, from 0.50 g(0.004 mol) of 6-chloro-1H-indole were prepared 0.76 g (95%) of1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone as a white solid.

2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide

To a stirred solution of1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.75 g) in 20 ml ofDMF at 0° C., were added 128 mg (1.1 eq.) of NaH (60% in oil). Themixture was stirred for 30 min. and then 0.32 ml (1.1 eq.) ofdimethylamino-acetyl chloride were added. The mixture was stirred anadditional hour and then poured onto water and extracted with ethylacetate. The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo to afford 598 mg (61%) of2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamideas a white solid.

6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid

Using a procedure similar to that described in J. Med. Chem. 1991, 34,140, from 0.50 g of2-[6-chloro-5-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamidewere prepared 0.38 g (76%) of6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid as awhite solid

Acid 3 6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure II, the alkylation of1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, with (commerciallyavailable) 2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 319.3 (M+H⁺).

6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-methyl-acetamidewas suspensed in DCE and treated with (2.2 eq.) of sodiumtrimethylsilanolate. After shaking at room temperature for 20 min, themixture was concentrated in vacuo and purified by prep. HPLC to give thetitle compound in 27% yield.

ES-MS m/e (%): 265.0 (M−H⁺).

Acid 46-Chloro-1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-1H-indole-3-carboxylicacid [6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid methylester

To a stirred solution of 6.65 g (0.0265 mol, 1 eq.) of1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 25 ml of DMF at0° C. were added 1.23 g of NaH (55% in oil, 0.0282 mol, 1.05 eq). After30 minutes, 4.31 g (0.0282 mol, 1.05 eq.) of bromo-acetic acid methylester were added and the temperature raised to RT, and stirring wascontinued overnight. The reaction was quenched by the addition of aq.HCl 0.1 M, and the product was extracted with EtOAc and the combinedorganic phases dried over Na₂SO₄. Recrystallisation in Et₂O/Heptaneafforded 6.90 g (80%) of[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid methylester as white crystals.

[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid

To as stirred solution of 2 g (6.3 mmol) of[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid methylester in 45 ml of THF/MeOH/H₂O 1/1/1, at 40° C., were added 0.79 g (18.9mmol, 3 eq.) of LiOH.H₂O. After 1 hour, the reaction mixture was dilutedin EtOAc, acidified with aq. HCl 1M. The organic phase were dried overNa₂SO₄, and concentrated under vacuo to afford 1.9 g (99%) of[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic acid as a whitesolid.

2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamide

An amide coupling between 0.99 g of[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-acetic andN1,N1-dimethyl-ethane-1,2-diamine according to the general procedure I,afforded 78 mg (6%) of2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamideas a white solid.

6-Chloro-1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-1H-indole-3-carboxylicacid

Using a similar procedure described in J. Med. Chem. 1991, 34, 140, from78 mg of2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamidewere prepared 65 mg (96%) of6-chloro-1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-1H-indole-3-carboxylicacid as a white solid.

Acid 56-Chloro-1-dimethylcarbamoylmethyl-5-methyl-1H-indole-3-carboxylic acid1-(6-Chloro-5-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

Using a procedure described in J. Med. Chem. 1991, 34, 140, from 0.250 g(0.002 mol) of 6-chloro-5-methyl-1H-indole were prepared 0.38 g (96%) of1-(6-chloro-5-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone as a whitesolid.

2-[6-Chloro-5-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide

To a stirred solution of1-(6-chloro-5-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.38 g) in10 ml of DMF at 0° C., were added 64 mg (1.1 eq.) of NaH (60% in oil).The mixture was stirred for 30 min. and then 0.16 ml (1.1 eq.) ofdimethylamino-acetyl chloride were added. The mixture was stirred anadditional hour and then poured onto water and extracted with ethylacetate. The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo to afford 300 mg (60%) of2-[6-chloro-5-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamideas a white solid.

6-Chloro-1-dimethylcarbamoylmethyl-5-methyl-1H-indole-3-carboxylic acid

Using a similar procedure described in J. Med. Chem. 1991, 34, 140, from0.280 g of2-[6-chloro-5-methyl-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamidewere prepared 0.18 g (76%) of6-chloro-1-dimethylcarbamoylmethyl-5-methyl-1H-indole-3-carboxylic acidas a white solid

Acid 6 5,6-Dichloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylicacid 1-(5,6-Dichloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

Using a procedure described in J. Med. Chem. 1991, 34, 140, from 0.120 g(0.64 mmol) of 5,6-dichloro-1H-indole were prepared 0.11 g (59%) of1-(5,6-dichloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone as a whitesolid.

2-[5,6-Dichloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamide

To a stirred solution of1-(5,6-dichloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (0.11 g) in 3 mlof DMF at 0° C., were added 18 mg (1.05 eq.) of NaH (60% in oil). Themixture was stirred for 30 min. and then 0.04 ml (1.0 eq.) ofdimethylamino-acetyl chloride were added. The mixture was stirred anadditional hour and then poured onto water and extracted with ethylacetate. The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo to afford 112 mg (78%) of2-[5,6-dichloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamideas a white solid.

5,6-Dichloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid

Using a similar procedure described in J. Med. Chem. 1991, 34, 140, from0.112 g of2-[5,6-dichloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N,N-dimethyl-acetamidewere prepared 0.047 g (49%) of5,6-dichloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid as awhite solid.

Acid 7 6-Chloro-2-methyl-1H-indole-3-carboxylic acid(6-Chloro-1H-indol-2-yl)-methanol

To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acidethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol)lithium aluminum hydride at 0° C. The reaction mixture was heated atreflux for 45 min and quenched by consecutive addition of 10 ml water,10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0° C. Theaqueous layer was extracted with tert-butyl methyl ether (3×100 ml). Thecombined organic layers were dried over sodium sulfate and concentratedin vacuo to give the crude title compound (1.64 g; 100%) as a whitesolid.

MS m/e (%): 180 (M−H⁺, 100).

6-Chloro-2-methyl-1H-indole

A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroaceticacid and 32.0 ml triethylsilane at 65° C. After 5 min, the reactionmixture was cooled to room temperature and quenched with water. The pHwas adjusted to 14 by the addition of aqueous sodium hydroxide solution(32%). The aqueous layer was extracted with tert-butyl methyl ether(3×200 ml). The combined organic layers were dried over sodium sulfateand concentrated in vacuo. The residue was purified byflash-chromatography (aminopropyl-modified silica gel, n-heptane/ethylacetate) to give the title compound (0.39 g; 27%) as a white solid.

MS m/e (%): 164 (M−H⁺, 100).

1-(6-Chloro-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone

To a solution of 0.38 g (2.3 mmol) 6-chloro-2-methyl-1H-indole in 20 ml1,2-dichloroethane at 0° C. were added 0.35 ml (2.5 mmol)trifluoroacetic anhydride. The reaction mixture was quenched withaqueous 2 M sodium carbonate solution after 30 min and extracted withdichloromethane (3×100 ml). The combined organic layers were dried oversodium sulfate and concentrated in vacuo to give the title compound(0.57 g; 95%) as an off-white solid.

MS m/e (%): 260 (M−H⁺, 100).

6-Chloro-2-methyl-1H-indole-3-carboxylic acid

A solution of 0.57 g (2.2 mmol)1-(6-chloro-2-methyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 21.7 ml(86.8 mmol) aqueous 4 M sodium hydroxide solution was heated at refluxfor 45 min. After cooling to room temperature the reaction mixture wasdiluted with water and extracted with tert-butyl methyl ether (2×50 ml).The aqueous layer was cooled to 0-5° C., acidified (pH 1-2) withconcentrated aqueous hydrochloric acid solution and extracted with ethylacetate (3×100 ml). The combined ethyl acetate layers were dried oversodium sulfate and concentrated in vacuo to give the title compound(0.14 g, 31%) as an off-white solid.

MS m/e (%): 208 (M−H⁺, 100).

Acid 8 5-Chloro-2-methyl-1H-indole-3-carboxylic acid

Using a procedure described in J. Med. Chem. 1991, 34, 140, from the5-chloro-2-methyl-1H-indole was prepared5-chloro-2-methyl-1H-indole-3-carboxylic acid.

Acid 9 Benzyl-2-methyl-1H-indole-3-carboxylic acid

To a stirred solution of 0.50 g (3.1 mmol)2-methyl-1H-indole-3-carboxylic acid (described in J. Heterocyclic Chem.1977, 14, 1123) in 5 ml DMF were added 0.27 g (6.75 mmol) of NaH (60% inoil). The mixture was stirred at RT for 30 min. and then 0.39 ml (3.28mmol) of benzyl bromid were added. The mixture was stirred an additionalhour and then poured onto water and extracted with ethyl acetate. Thecombined organic phases were dried over Na₂SO₄ and concentrated invacuo. Crystallization in Et₂O afforded 0.61 g (78%) of1-benzyl-2-methyl-1H-indole-3-carboxylic acid as a white solid.

Acid 10 3,4-Dihydro-1H-pyrazino[1,2-a]indole-2,10-dicarboxylic acid2-tert-butyl ester10-(2,2,2-Trifluoro-acetyl)-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

To a stirred solution of 0.21 ml (1.5 mmol) trifluoroacetic anhydride in7 ml 1,2-dichloroethane was added at 0° C. a solution of 0.37 g (1.4mmol) 3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butylester and a solution of 0.23 ml (1.63 mmol) triethylamine in 3 ml1,2-dichloroethane. After stirring for 30 min the reaction mixture wasquenched with saturated aqueous sodium hydrogen carbonate solution andextracted with dichloromethane (2×100 ml). The combined organic layerswere dried over sodium sulfate, concentrated in vacuo and purified byflash chromatography (n-heptane/ethyl acetate) to give the titlecompound (0.288 g, 58%) as a light yellow solid.

MS m/e (%): 369 (M+H⁺, 27).

3,4-Dihydro-1H-pyrazino[1,2-a]indole-2,10-dicarboxylic acid 2-tert-butylester

To a solution of 0.29 g (0.77 mmol)10-(2,2,2-trifluoro-acetyl)-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester in 7 ml N,N-dimethylformamide were subsequentlyadded 0.22 g (4.6 mmol) sodium hydride (50% in oil) and a solution of0.070 ml (3.9 mmol) water in 1 ml N,N-dimethylformamide at roomtemperature. The reaction mixture was diluted with tert-butyl methylether after 2 h and extracted with 1 M sodium hydroxide solution (2×30ml). The combined aqueous layers were acidified (pH 1-2) with 2 Mhydrochloric acid at 0° C. and extracted with tert-butyl methyl ether(3×50 ml). The combined organic layers were dried over sodium sulfateand concentrated in vacuo to give the title compound (0.21 g, 86%) as alight brown solid.

MS m/e (%): 315 (M−H⁺, 100).

Examples of Compounds of Formula I-a and I-a′ Example 1Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine (commerciallyavailable),

Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 425.5 (M+H⁺).

Example 2Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-Phenyl-1,2,3,6-tetrahydro-pyridine (commercially available),

Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 407.5 (M+H⁺).

Example 3Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(2-Methoxy-phenyl)-1,2,3,6-tetrahydro-pyridine (described inU.S. Pat. No. 6,326,381),

Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 437.6 (M+H⁺).

Example 4(6-Chloro-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-Phenyl-1,2,3,6-tetrahydro-pyridine (commercially available),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 337.4 (M+H⁺).

Example 5(6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine (commerciallyavailable),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 355.4 (M+H⁺).

Example 6(6-Chloro-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

Following general procedure I, the coupling of (commercially available)4-phenyl-1,2,3,6-tetrahydro-pyridine, with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 337.4 (M+H⁺).

Example 7(6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 355.4 (M+H⁺).

Example 8(6-Chloro-1H-indol-3-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 371.4 (M+H⁺).

Example 9Benzyl-2-methyl-1H-indol-3-yl)-(5-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone

Following general procedure I, the coupling of (commercially available)5-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (described in WO2005077912) with 1-benzyl-2-methyl-1H-indole-3-carboxylic acid gave thetitle compound.

ES-MS m/e (%): 421.6 (M+H⁺).

Examples of Compounds of Formula I-b Example 10(4-Benzyl-4-hydroxy-piperidin-1-yl)-(1-benzyl-2-methyl-1H-indol-3-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-Benzyl-piperidin-4-ol (commercially available),

Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 439.5 (M+H⁺).

Example 11(4-Benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-chloro-benzyl)-2-methyl-1-indol-3-yl]-methanone

(4-Benzyl-4-hydroxy-piperidin-1-yl)-(2-methyl-1H-indol-3-A-methanone

To a stirred solution of 0.1 g (0.57 mmol)2-methyl-1H-indole-3-carboxylic acid in 10 ml CH₂Cl₂ were added 0.14 g(0.73 mmol) EDC, 0.10 g (0.73 mmol) HOBt, 90 μl (0.63 mmol) Et₃N and0.11 g (0.57 mmol) 4-benzyl-piperidin-4-ol. The mixture was stirredovernight at RT and then poured onto water and extracted with CH₂Cl₂.The combined organic phases were dried over Na₂SO₄ and concentrated invacuo. Flash chromatography (ethyl acetate) afforded 0.15 g (75%) of(4-benzyl-4-hydroxy-piperidin-1-yl)-(2-methyl-1H-indol-3-yl)-methanoneas a white solid.

ES-MS m/e (%): 349 (M+H⁺).

(4-Benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-chloro-benzyl)-2-methyl-1H-indol-3-yl]-methanone

To a stirred solution of 40 mg (0.11 mmol) of(4-benzyl-4-hydroxy-piperidin-1-yl)-(2-methyl-1H-indol-3-yl)-methanonein 5 ml DMF were added 5 mg (0.11 mmol) NaH (60% in oil). The mixturewas stirred at RT for 30 min. and then 28 mg (0.13 mmol) of1-bromomethyl-2-chloro-benzene were added. The mixture was stirred anadditional hour and then poured onto water and extracted with ethylacetate. The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo. Preparative HPLC (30% CH₃CN/H₂O) afforded 33 mg(61%) of(4-benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-chloro-benzyl)-2-methyl-1H-indol-3-yl]-methanoneas a white solid.

ES-MS m/e (%): 473.4 (M+H⁺).

Example 12Benzyl-5-chloro-2-methyl-1H-indol-3-yl)-(4-benzyl-4-hydroxy-piperidin-1-yl)-methanone

(4-benzyl-4-hydroxy-piperidin-1-yl)-(5-chloro-2-methyl-1H-indol-3-yl)-methanone

Using the procedure described for the preparation of(4-benzyl-4-hydroxy-piperidin-1-yl)-(2-methyl-1H-indol-3-yl)-methanone,from 40 mg (0.19 mmol) of 5-chloro-2-methyl-1H-indole-3-carboxylic acidand 40 mg (0.21 mmol) of 4-benzyl-piperidin-4-ol were prepared 45 mg(62%) of(4-benzyl-4-hydroxy-piperidin-1-yl)-(5-chloro-2-methyl-1H-indol-3-yl)-methanoneas a white solid.

ES-MS m/e (%): 383 (M+H⁺).

(1-benzyl-5-chloro-2-methyl-1H-indol-3-yl)-(4-benzyl-4-hydroxy-piperidin-1-yl)-methanone

Using the procedure described for the preparation of(4-benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-chloro-benzyl)-2-methyl-1H-indol-3-yl]-methanone,from 13 mg (0.034 mmol) of(4-benzyl-4-hydroxy-piperidin-1-yl)-(5-chloro-2-methyl-1H-indol-3-yl)-methanoneand 5.8 mg (0.034 mmol) of benzyl bromide were prepared 14 mg (87%) of(1-benzyl-5-chloro-2-methyl-1H-indol-3-yl)-(4-benzyl-4-hydroxy-piperidin-1-yl)-methanoneas a white solid.

ES-MS m/e (%): 473.3 (M+H⁺).

Example 13(4-Benzyl-4-hydroxy-piperidin-1-yl)-[5-chloro-1-(3-methoxy-benzyl)-2-methyl-1H-indol-3-yl]-methanone

Using the procedure described for the preparation of(4-benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-chloro-benzyl)-2-methyl-1H-indol-3-yl]-methanone,from 13 mg (0.034 mmol) of(4-benzyl-4-hydroxy-piperidin-1-yl)-(5-chloro-2-methyl-1H-indol-3-yl)-methanoneand 6.8 mg (0.034 mmol) of 1-bromomethyl-3-methoxy-benzene were prepared11 mg (65%) of(4-benzyl-4-hydroxy-piperidin-1-yl)-[5-chloro-1-(3-methoxy-benzyl)-2-methyl-1H-indol-3-yl]-methanoneas a white solid.

ES-MS m/e (%): 503.5 (M+H⁺).

Example 14(4-Benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-methoxy-benzyl)-2-methyl-1-indol-3-yl]-methanone

Using the procedure described for the preparation of(4-benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-chloro-benzyl)-2-methyl-1H-indol-3-yl]-methanone,from 28 mg (0.080 mmol) of(4-benzyl-4-hydroxy-piperidin-1-yl)-(2-methyl-1H-indol-3-yl)-methanoneand 15 mg (0.096 mmol) of 1-chloromethyl-2-methoxy-benzene were prepared29 mg (77%) of(4-benzyl-4-hydroxy-piperidin-1-yl)-[1-(2-methoxy-benzyl)-2-methyl-1H-indol-3-yl]-methanoneas a white solid.

ES-MS m/e (%): 469.6 (M+H⁺).

Example 15Benzyl-2-methyl-1H-indol-3-yl)-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(3-Fluoro-phenoxy)-piperidine (described in US260294700),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 443.6 (M+H⁺).

Example 16Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Chloro-phenyl)-piperidin-4-ol (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid

ES-MS m/e (%): 459.5 (M+H⁺).

Example 17Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-bromo-phenyl)-4-hydroxy-piperidin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Bromo-phenyl)-piperidin-4-ol (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 505.5 (M+H⁺).

Example 18Benzyl-2-methyl-1H-indol-3-yl)-(4-hydroxy-4-phenyl-piperidin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-Phenyl-piperidin-4-ol (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 425.6 (M+H⁺).

Example 19Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Fluoro-phenyl)-piperidin-4-ol (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 443.6 (M+H⁺).

Example 20Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol(commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid

ES-MS m/e (%): 527.5 (M+H⁺).

Example 21(4-Benzo[1,3]dioxol-5-yl-4-hydroxy-piperidin-1-yl)-(1-benzyl-2-methyl-1H-indol-3-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-Benzo[1,3]dioxol-5-yl-piperidin-4-ol (described in WO9709311),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 469.6 (M+H⁺).

Example 22Benzyl-2-methyl-1H-indol-3-yl)-(4-hydroxy-4-p-tolyl-piperidin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-p-Tolyl-piperidin-4-ol (described in EP445701),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 439.6 (M+H⁺).

Example 23Benzyl-2-methyl-1H-indol-3-yl)-[4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(3-Trifluoromethyl-phenyl)-piperidin-4-ol (commerciallyavailable),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 493.6 (M+H⁺).

Example 24Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-piperidin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-Phenyl-piperidine (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid

ES-MS m/e (%): 409.5 (M+H⁺).

Example 25 (6-Chloro-1H-indol-3-yl)-(4-phenyl-piperidin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-Phenyl-piperidine (commercially available),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 339.4 (M+H⁺).

Example 26(6-Chloro-1H-indol-3-yl)-[4-hydroxy-4-(3-trifluoromethyl-phenyl)-piperidin-1-yl]-methanol

Amide coupling according to general procedure I:

Amine: 4-(3-Trifluoromethyl-phenyl)-piperidin-4-ol (commerciallyavailable),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 423.4 (M+H⁺).

Example 271-(6-Chloro-1H-indole-3-carbonyl)-4-phenyl-piperidine-4-carbonitrile

Amide coupling according to general procedure I:

Amine: 4-Phenyl-piperidine-4-carbonitrile (commercially available),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 364.4 (M+H⁺).

Example 28(6-Chloro-1H-indol-3-yl)-(4-hydroxy-4-p-tolyl-piperidin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-p-Tolyl-piperidin-4-ol (described in EP445701),Acid: 6-chloro-1H-indole-3-carboxylic acid

ES-MS m/e (%): 369.4 (M+H⁺).

Example 29(6-Chloro-1H-indol-3-yl)-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Chloro-phenyl)-piperidin-4-ol (commercially available),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 389.4 (M⁺).

Example 30(6-Chloro-1H-indol-3-yl)-[4-(4-chloro-3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Chloro-3-trifluoromethyl-phenyl)-piperidin-4-ol(commercially available),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 457.4 (M⁺).

Example 31(4-Benzo[1,3]dioxol-5-yl-4-hydroxy-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-Benzo[1,3]dioxol-5-yl-piperidin-4-ol (described in WO9709311),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 399.4 (M+H⁺).

Example 32[4-(4-Bromo-phenyl)-4-hydroxy-piperidin-1-yl]-(6-chloro-1H-indol-3-yl)-methanone

Amide coupling according to general procedure I:

Amine: 4-(4-Bromo-phenyl)-piperidin-4-ol (commercially available),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 435.3 (M⁺).

Example 33 [1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-carbamicacid tert-butyl ester

Amide coupling according to general procedure I:

Amine: Piperidin-4-yl-carbamic acid tert-butyl ester (commerciallyavailable),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 378.3 (M+H⁺).

Example 34N-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-2-fluoro-benzamide

(4-Amino-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone

To a stirred solution of 0.50 g (1.32 mmol) of[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-carbamic acidtert-butyl ester (the preparation of which has been described in example31) in CH₂Cl₂ (10 ml), were added 2 ml of TFA. The mixture was stirred 2hours, then poured onto an aqueous solution of sat. NaHCO₃ and thenextracted with ethyl acetate. The combined organic phases were driedover Na₂SO₄ and concentrated in vacuo, to afford 0.25 g (68%) of(4-amino-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone as a lightbrown solid.

ES-MS m/e (%): 78.1 (M+H⁺).

N-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-2-fluoro-benzamide

To a stirred solution of 50 mg (0.36 mmol) 2-fluoro-benzoic acid in 5 mlCH₂Cl₂ were added 90 mg (0.47 mmol) EDC, 63 mg (0.47 mmol) HOBt, 60 μl(0.47 mmol) Et₃N and 100 mg (0.36 mmol)(4-amino-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone. The mixturewas stirred overnight at RT and then poured onto water and extractedwith CH₂Cl₂. The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuo. Flash chromatography (ethyl acetate) afforded 82mg (57%)N-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-2-fluoro-benzamideof as a white solid.

ES-MS m/e (%): 400.3 (M+H⁺).

Example 351-[1-(1-Cyclohexylmethyl-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one

Following general procedure I, the coupling of (commercially available)4-(4-fluoro-phenyl)-piperidine with1-benzyl-2-methyl-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 427.6 (M+H⁺).

Example 36(6-Chloro-1H-indol-3-yl)-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(4-chloro-phenyl)-piperidin-4-ol with 6-chloro-1H-indole-3-carboxylicacid gave the title compound.

ES-MS m/e (%): 389.4 (M+H⁺).

Example 37(6-Chloro-1H-indol-3-yl)-[4-(4-nitro-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(4-nitro-phenyl)-piperidine with 6-chloro-1H-indole-3-carboxylic acidgave the title compound.

ES-MS m/e (%): 384.4 (M+H⁺).

Example 38(6-Chloro-1H-indol-3-yl)-[4-(3-chloro-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(3-chloro-phenyl)-piperidine with 6-chloro-1H-indole-3-carboxylic acidgave the title compound.

ES-MS m/e (%): 373.3 (M+H⁺).

Example 39(6-Chloro-1H-indol-3-yl)-[4-(2-hydroxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)2-piperidin-4-yl-phenol with 6-chloro-1H-indole-3-carboxylic acid gavethe title compound.

ES-MS m/e (%): 355.4 (M+H⁺).

Example 40(6-Chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(2,6-dimethoxy-phenyl)-piperidine with 6-chloro-1H-indole-3-carboxylicacid gave the title compound.

ES-MS m/e (%): 399.2 (M+H⁺).

Example 41(6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(4-fluoro-phenyl)-piperidine with 6-chloro-1H-indole-3-carboxylic acidgave the title compound.

ES-MS m/e (%): 357.4 (M+H⁺).

Example 42(6-Chloro-1H-indol-3-yl)-(4-methoxy-4-phenyl-piperidin-1-yl)-methanone

Following general procedure I, the coupling of4-methoxy-4-phenyl-piperidine (described in WO 9800400) with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 369.4 (M+H⁺).

Example 432-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with commercially available2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 484.3 (M+H⁺).

Example 442-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-pyridin-2-yl-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with commercially available2-chloro-1-pyridin-2-yl-ethanone gave the title compound.

ES-MS m/e (%): 518.4 (M+H⁺).

Example 45 (6-Chloro-1-pyridin-4-ylmethyl-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with commercially available4-chloromethyl-pyridine gave the title compound.

ES-MS m/e (%): 490.3 (M+H⁺).

Example 46 (6-Chloro-1-pyridin-3-ylmethyl-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with commercially available3-chloromethyl-pyridine gave the title compound.

ES-MS m/e (%): 490.3 (M+H⁺).

Example 47 (6-Chloro-1-pyridin-2-ylmethyl-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with methanesulfonic acidpyridin-2-ylmethyl ester (described in WO 9955318) gave the titlecompound.

ES-MS m/e (%): 490.3 (M+H⁺).

Example 48[6-Chloro-1-(6-chloro-pyridin-3-ylmethyl)-1H-indol-3-yl]-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with methanesulfonic acid6-chloro-pyridin-3-ylmethyl ester (described in Journal of OrganicChemistry (1999), 64(23), 8576-8581) gave the title compound.

ES-MS m/e (%): 524.2 (M+H⁺).

Example 49{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid tert-butyl ester

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid tert-butyl ester gave the title compound.

ES-MS m/e (%): 513.3 (M+H⁺).

Example 506-Chloro-1-pyrazin-2-ylmethyl-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with methanesulfonic acidpyrazin-2-ylmethyl ester (described in WO 2002064574) gave the titlecompound.

ES-MS m/e (%): 491.1 (M+H⁺).

Example 51[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)1-chloromethyl-3,5-difluoro-benzene gave the title compound.

ES-MS m/e (%): 525.3 (M+H⁺).

Example 52[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)(2-chloro-ethyl)-dimethyl-amine gave the title compound.

ES-MS m/e (%): 470.5 (M+H⁺).

Example 53(6-Chloro-1H-indol-3-yl)-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of4-(2-isopropoxy-phenyl)-piperidine (described in Journal of MedicinalChemistry (1998), 41(12), 1997-2009) with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 397.1 (M+H⁺).

Example 54(6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(2-methoxy-phenyl)-piperidine with 6-chloro-1H-indole-3-carboxylicacid gave the title compound.

ES-MS m/e (%): 367.0 (M+H⁺).

Example 552-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 539.6 (M+H⁺).

Example 56[6-Chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)1-chloromethyl-3,5-difluoro-benzene gave the title compound.

ES-MS m/e (%): 495.2 (M+H⁺).

Example 572-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 454.3 (M+H⁺).

Example 582-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 509.3 (M+H⁺).

Example 59{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid tert-butyl ester

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid tert-butyl ester gave the title compound.

ES-MS m/e (%): 483.3 (M+H⁺).

Example 602-{6-Chloro-3-[4-cyano-4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Amide coupling according to general procedure I:

Amine: 4-(2-Methoxy-phenyl)-piperidine-4-carbonitrile (described inWO2003053361),Acid: 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 479.1 (M+H⁺).

Example 612-{6-Chloro-3-[4-cyano-4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Amide coupling according to general procedure I:

Amine: 4-(2-Fluoro-phenyl)-piperidine-4-carbonitrile (described inTetrahedron 2004, 4875),Acid: 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 467.1 (M+H⁺).

Example 622-{3-[4-(2,6-Dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 450.6 (M+H⁺).

Example 63[6-Chloro-1-(2-methyl-pyridin-4-ylmethyl)-1H-indol-3-yl]-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with methanesulfonic acid2-methyl-pyridin-4-ylmethyl ester (prepared by mesylation of thecommercially available (2-methyl-pyridin-4-yl)-methanol) gave the titlecompound.

ES-MS m/e (%): 504.1 (M+H⁺).

Example 642-{3-[4-(2,6-Dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 505.4 (M+H⁺).

Example 652-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 457.5 (M+H⁺).

2-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid with (commercially available) N¹,N¹-dimethyl-ethane-1,2-diaminegave the title compound.

ES-MS m/e (%): 527.3 (M+H⁺).

Example 662-{6-Chloro-3-[4-(2-isopropoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 482.6 (M+H⁺).

Example 672-{6-Chloro-3-[4-(2-isopropoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-isopropoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 537.6 (M+H⁺).

Example 682-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 427.5 (M+H⁺).

2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid with (commercially available) piperazine-1-carboxylic acidtert-butyl ester gave, after treatment with TFA and neutralisation, thetitle compound.

ES-MS m/e (%): 495.5 (M+H⁺).

Example 692-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)piperazine-1-carboxylic acid tert-butyl ester gave, after treatment withTFA and neutralisation, the title compound.

ES-MS m/e (%): 525.5 (M+H⁺).

Example 70(6-Chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone4-(5-Bromo-2,3-dihydro-benzofuran-7-yl)-pyridine

4-Bromopyridine or hydrochloride salt thereof was dissolved in DME underargon and Pd(Ph₃P)₄ (3 mol %) was added. The mixture was stirred for 10min at 50° C. To this solution was added (commercially available)5-bromo-2,3-dihydrobenzo[b]furan-7-boronic acid dissolved in a minimumamount of EtOH/DME 1:2 followed by 2N Na₂CO₃. The reaction mixture wasrefluxed (110° C.) under stirring for 2 h. The flask was cooled to RT,the mixture was treated with sat. aq. NH₄Cl solution and extracted withCHCl₃. Evaporation and purification by SiO₂ gel chromatography(hexane/ethyl acetate: 4/1) gave the title compound in 76% yield.

ES-MS m/e (%): 275.9 (M+H⁺).

1-Benzyl-4-(5-bromo-2,3-dihydro-benzofuran-7-yl)-1,2,3,6-tetrahydro-pyridine

To a solution of 4-(5-bromo-2,3-dihydro-benzofuran-7-yl)-pyridine intoluene was added benzyl bromide (1 eq.) and the reaction mixture wasstirred under reflux for 14 h. Reaction was monitored by TLC(CH₂Cl₂/MeOH 95:5) and revealed total conversion to an intermediate.Complete evaporation of the solvent gave a white solid. The solid wasdissolved in MeOH under argon and cooled down to 0° C., NaBH₄ (2.05 eq.)was added portion-wise (exothermic reaction) and the reaction mixturewas stirred for 3 h at RT. Evaporation of MeOH, redissolution in CH₂Cl₂and sequential washing with 1N NaHCO₃ and brine, followed bypurification by SiO₂ gel chromatography (CH₂Cl₂/MeOH: 98/2) gave 71%yield of the title compound.

ES-MS m/e (%): 370.0 (M+H⁺).

4-(2,3-Dihydro-benzofuran-7-yl)-piperidine

To a solution of1-benzyl-4-(5-bromo-2,3-dihydro-benzofuran-7-yl)-1,2,3,6-tetrahydro-pyridinein EtOH and 4N HCl was added 40 wt % of 10% Pd/C catalyst. The reactionflask was charged with H2 (3.5 bar) and then stirred overnight at 50° C.The reaction mixture was filtered over Celite under argon. The solventswere evaporated and the product was partitioned between CH₂Cl₂ and aq.K₂CO₃. The organic phase was dried over Na₂SO₄ and evaporated to givethe title compound in 81% yield.

ES-MS m/e (%): 204.3 (M+H⁺).

(6-Chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of4-(2,3-dihydro-benzofuran-7-yl)-piperidine (described herein below) with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 381.1 (M+H⁺).

Example 712-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 521.6 (M+H⁺).

Example 722-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 466.6 (M+H⁺).

Example 732-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 437.1 (M−H⁺).

2-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid with (commercially available) N¹,N¹-dimethyl-ethane-1,2-diaminegave the title compound.

ES-MS m/e (%): 509.6 (M+H⁺).

Example 742-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared described herein) with (commercially available)piperazine-1-carboxylic acid tert-butyl ester gave, after treatment withTFA and neutralisation, the title compound.

ES-MS m/e (%): 507.0 (M+H⁺).

Example 752-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-5-methyl-indol-1-yl}-N,N-dimethyl-acetamide

Amide coupling according to general procedure I:

Amine: 4-(2-Methoxy-phenyl)-piperidine (commercially available),Acid: 6-Chloro-1-dimethylcarbamoylmethyl-5-methyl-1H-indole-3-carboxylicacid,

ES-MS m/e (%): 468.3 (M+H⁺).

Example 762-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 451.7 (M+H⁺).

Example 77N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)(2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatmentwith HCl and neutralisation, the title compound.

ES-MS m/e (%): 481.3 (M+H⁺).

Example 782-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available) ammonia in THF,gave the title compound.

ES-MS m/e (%): 438.2 (M+H⁺).

Example 792-{6-Chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)(2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, aftertreatment with TFA and neutralisation, the title compound.

ES-MS m/e (%): 495.5 (M+H⁺).

Example 802-{5,6-Dichloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Amide coupling according to general procedure I:

Amine: 4-(2-Methoxy-phenyl)-piperidine (commercially available),Acid: 5,6-Dichloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylicacid,

ES-MS m/e (%): 488.5 (M+H⁺).

Example 812-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available) ammonia in THF gavethe title compound.

ES-MS m/e (%): 456.2 (M+H⁺).

Example 822-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone(prepared herein) with (commercially available)2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 470.2 (M+H⁺).

Example 832-{6-Chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)(2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, aftertreatment with TFA and neutralisation, the title compound.

ES-MS m/e (%): 513.5 (M+H⁺).

Example 84N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)(2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatmentwith HCl and neutralisation, the title compound.

ES-MS m/e (%): 499.5 (M+H⁺).

Example 85(6-Chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone4-(2-Trifluoromethoxy-phenyl)-pyridine

To a solution of (commercially available)(1-bromo-2-trifluoromethoxy-benzene) in DME (first degased with argon)under argon was added 3 mol % Pd(PPh₃)₄, pyridyl-4-boronic acid and 2NNa₂CO₃, the resulting reaction mixture was vigorously stirred underreflux. After 5 h at reflux, reaction as monitored by TLC showedcompletion. Two phases were separated, evaporation of most of the DME,redissolution of the residue in EtOAc and washing with aq. NaOH followedby evaporation gave a yellow oil. Flash Chromatography on SiO2 gel witha mixture of CH₂Cl₂/MeOH gave the title compound in 51% yield.

ES-MS m/e (%): 239.9 (M+H⁺).

1-Benzyl-4-(2-trifluoromethoxy-phenyl)-1,2,3,6-tetrahydro-pyridine

To a solution of 4-(2-trifluoromethoxy-phenyl)-pyridine in toluene wasadded (1 eq.) benzyl bromide, and reaction mixture was stirred underreflux for 2 h. Reaction was monitored by TLC (CH₂Cl₂/MeOH 95:5) andrevealed total conversion to the first intermediate. Completeevaporation of solvent gave a white solid which was pure enough to carryout the next step. The white solid was dissolved in MeOH under argon andcooled down to 0° C., (4 eq.) NaBH₄ was added portion-wise (exothermicreaction). The reaction mixture was then stirred for 3 h at RT, reactionagain monitored by TLC (CH₂Cl₂/MeOH 95:5) and revealed total conversion.Evaporation of MeOH, redissolution in CH₂Cl₂, and washing with 1N NaHCO₃then brine, and evaporation, followed by SiO2 gel chromatography(CH₂Cl₂/MeOH) gave the title compound in 61% yield.

ES-MS m/e (%): 334.3 (M+H⁺).

4-(2-Trifluoromethoxy-phenyl)-piperidine

To a solution of1-benzyl-4-(2-trifluoromethoxy-phenyl)-1,2,3,6-tetrahydro-pyridine

(described herein below) in EtOH was added (0.2 wt %) 10% Pd/C, followedby (5 eq.) TFA in a sealed tube. The reaction mixture was stirred at 50°C. under 3.0 bar of H₂ for 12 h. The reaction mixture was filtered overCelite and the filtrate evaporated down to dryness. Redissolution inEtOAc, washing with 1N NaHCO3 and concentration gave the crude productwhich was directly used for the next step.

ES-MS m/e (%): 246.6 (M+H⁺).

(6-Chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of4-(2-trifluoromethoxy-phenyl)-piperidine with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 423.3 (M+H⁺).

Example 86(6-Chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(2-trifluoromethyl-phenyl)-piperidine (described herein) with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 407.1 (M+H⁺).

Example 87[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone(prepared herein) with (commercially available)(2-chloro-ethyl)-dimethyl-amine gave the title compound.

ES-MS m/e (%): 452.2 (M+H⁺).

Example 882-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 563.3 (M+H⁺).

Example 892-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 481.3 (M+H⁺).

2-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)N¹,N¹-dimethyl-ethane-1,2-diamine gave the title compound.

ES-MS m/e (%): 551.5 (M+H⁺).

Example 902-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Analogous to general procedure I, the coupling of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone(prepared herein) with (commercially available)2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 494.5 (M+H⁺).

Example 912-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available) ammonia in THF,gave the title compound.

ES-MS m/e (%): 480.3 (M+H⁺).

Example 922-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared described herein) with (commercially available)piperazine-1-carboxylic acid tert-butyl ester gave, after treatment withTFA and neutralisation, the title compound.

ES-MS m/e (%): 548.7 (M+H⁺).

Example 932-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared described herein) with (commercially available)(2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, aftertreatment with TFA and neutralisation, the title compound.

ES-MS m/e (%): 536.7 (M+H⁺).

Example 94N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared described herein) with (commercially available)(2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatmentwith HCl and neutralisation, the title compound.

ES-MS m/e (%): 522.7 (M+H⁺).

Example 952-{6-Chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone(prepared herein) with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 508.4 (M+H⁺).

Example 962-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone(prepared herein) with (commercially available)2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 477.7 (M+H⁺).

Example 972-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone(prepared herein) with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 546.8 (M+H⁺).

Example 982-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 481.3 (M+H⁺).

2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid with (commercially available) ammonia in THF, gave the titlecompound.

ES-MS m/e (%): 464.6 (M+H⁺).

Example 992-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanonehydrochloride

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)piperazine-1-carboxylic acid tert-butyl ester gave, after treatment withHCl, the title compound.

ES-MS m/e (%): 532.7 (M+H⁺).

Example 1002-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamidehydrochloride

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)(2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, aftertreatment with HCl the title compound.

ES-MS m/e (%): 521.3 (M+H⁺).

Example 101N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamidehydrochloride

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)(2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatmentwith HCl, the title compound.

ES-MS m/e (%): 507.3 (M+H⁺).

Example 1022-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Analogous to general procedure I, the coupling of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone(prepared herein) with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 491.7 (M+H⁺).

Example 103N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamidehydrochloride

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)N¹,N¹-dimethyl-ethane-1,2-diamine, gave the title compound.

ES-MS m/e (%): 534.8 (M+H⁺).

Example 104[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-ethylamine gave the title compound.

ES-MS m/e (%): 424.5 (M+H⁺).

Example 105[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone(prepared herein) with (commercially available) 2-chloro-ethylamine gavethe title compound.

ES-MS m/e (%): 466.4 (M+H⁺).

Example 1062-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure II, the alkylation of(6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 440.4 (M+H⁺).

Example 107[6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)(2-chloro-ethyl)-methyl-amine gave the title compound.

ES-MS m/e (%): 438.4 (M+H⁺).

Example 108[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)(2-chloro-ethyl)-dimethyl-amine gave the title compound.

ES-MS m/e (%): 440.3 (M+H⁺).

Example 109[6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)(2-chloro-ethyl)-methyl-amine gave the title compound.

ES-MS m/e (%): 426.3 (M+H⁺).

Example 110[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-ethylamine gave the title compound.

ES-MS m/e (%): 412.3 (M+H⁺).

Example 1112-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide(6-Chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)4-(2-fluoro-phenyl)-piperidine (described herein below) with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 357.3 (M+H⁺).

2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone,with (commercially available) 2-chloro-N-methyl-acetamide gave the titlecompound.

ES-MS m/e (%): 428.2 (M+H⁺).

Example 112[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-ethylamine gave the title compound.

ES-MS m/e (%): 400.1 (M+H⁺).

Example 1132-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 413.0 (M−H⁺).

2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamide

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid, with (commercially available) ammonia in THF gave the titlecompound.

ES-MS m/e (%): 414.2 (M+H⁺).

Example 1142-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone(preparation described herein below), with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 442.3 (M+H⁺).

Example 115[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)(2-chloro-ethyl)-dimethyl-amine gave the title compound.

ES-MS m/e (%): 428.2 (M+H⁺).

Example 1162-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (preparation described herein), with (commercially available)N¹,N¹-dimethyl-ethane-1,2-diamine gave the title compound.

ES-MS m/e (%): 485.2 (M+H⁺).

Example 1172-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 497.2 (M+H⁺).

Example 1182-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanonehydrochloride

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (preparation described herein), with (commercially available)piperazine-1-carboxylic acid tert-butyl ester gave, after treatment withHCl, gave the title compound.

ES-MS m/e (%): 483.2 (M+H⁺).

Example 1192-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamidehydrochloride

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (preparation described herein), with (commercially available)(2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, aftertreatment with HCl, the title compound.

ES-MS m/e (%): 471.2 (M+H⁺).

Example 120N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetamidehydrochloride

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-aceticacid (preparation described herein), with (commercially available)(2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatmentwith HCl the title compound.

ES-MS m/e (%): 457.2 (M+H⁺).

Example 121(6-Chloro-1H-indol-3-yl)-(3,4,5,6-tetrahydro-2H-[4,4]bipyridinyl-1-yl)-methanone

Following general procedure I, the coupling of (commercially available)1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 340.1 (M+H⁺).

Example 1222-[6-Chloro-3-(3,4,5,6-tetrahydro-2H-[4,4]bipyridinyl-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)2-piperazin-1-yl-nicotinonitrile with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid gave thetitle compound.

ES-MS m/e (%): 425.2 (M+H⁺).

Example 123(6-Chloro-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone

To a solution of 0.040 g (0.19 mmol)6-chloro-2-methyl-1H-indole-3-carboxylic acid, 0.069 ml (0.40 mmol)N,N-diisopropylethylamine and 0.061 g (0.19 mmol)2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroboratein 1 ml dry N,N-dimethylformamide were added 0.038 g (0.20 mmol)4-(2-methoxy-phenyl)-piperidine at room temperature. After stirring for1 h the reaction mixture was quenched with 0.5 M aqueous sodiumhydroxide solution (20 ml) and extracted with ethyl acetate (2×30 ml).The combined organic layers were washed with water (2×30 ml) and brine(1×30 ml), dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash chromatography (n-heptane/ethyl acetate)to give the title compound (0.050 g; 69%) as a white solid.

MS m/e (%): 381 (M−H⁺, 100).

Example 124(6-Chloro-1-methanesulfonyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone

To a solution of 0.035 g (0.09 mmol)(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanonein 2 ml N,N-dimethylformamide were added 0.005 g (0.10 mmol) sodiumhydride (50% in oil). After 45′, 0.008 ml (0.10 mmol) methanesulfonylchloride were added. The reaction mixture was quenched with water after3 h and extracted with ethyl acetate (2×50 ml). The combined organiclayers were washed with water (2×30 ml) and brine (1×30), dried oversodium sulfate and concentrated to dryness. The residue waschromatographed (loaded as a solution in toluene; Flashpac 5 g;n-heptane/ethyl acetate 100:0->75:25) to give the title compound (0.007g; 17%) as a light yellow solid.

MS m/e (%): 447 (M+H⁺, 100).

Example 125 2-{6-Chloro-3-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)5-fluoro-3-piperidin-4-yl-benzo[d]isoxazole with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 469.1 (M+H⁺).

Example 1262-{6-Chloro-3-[4-(2-fluoro-phenyl)-4-hydroxy-piperidine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of4-(2-fluoro-phenyl)-piperidin-4-ol (described in WO 2005118587) with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 444.1 (M+H⁺).

Example 1272-[6-Chloro-3-(3,4,5,6-tetrahydro-2H-[4,4]bipyridinyl-1-carbonyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)2-piperazin-1-yl-nicotinonitrile with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 411.2 (M+H⁺).

Example 128 10-[4-(2-Methoxy-phenyl)-piperidine-1-carbonyl]-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

To a solution of 0.10 g (0.32 mmol)3,4-dihydro-1H-pyrazino[1,2-a]indole-2,10-dicarboxylic acid 2-tert-butylester, 0.067 g (0.35 mmol) 4-(2-methoxyphenyl)-piperidine and 0.051 g(0.38 mmol) 1-hydroxybenzotriazole in 3.5 ml N,N-dimethylformamide wereadded 0.073 g (0.38 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride at room temperature. After stirring for 3 h the reactionmixture was diluted with saturated aqueous ammonium chloride solutionand extracted with tert-butyl methyl ether (2×50 ml). The combinedorganic layers were washed with 1 M sodium hydroxide solution (1×30 ml)and water (1×30 ml), dried over sodium sulfate, concentrated in vacuoand purified by flash-chromatography (aminopropyl-modified silica gel,n-heptane/ethyl acetate) to give the title compound (0.087 g, 56%) as alight yellow solid.

MS m/e (%): 490 (M+H⁺, 47).

Example 129 [4-(2-Methoxy-phenyl)-piperidin-1-yl]-(1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanonehydrochloride

A mixture of 0.085 g (0.17 mmol)10-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester and 1.4 ml of a 1.25 M solution of hydrochloricacid (1.7 mmol) in methanol was stirred for 15 min at 50° C. Thereaction mixture was concentrated in vacuo to give the title compound(0.072 g, 97%) as a light yellow solid.

MS m/e (%): 390 (M+H⁺, 100).

Example 130 [4-(2-Methoxy-phenyl)-piperidin-1-yl]-(2-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanone

A solution of 0.040 g (0.094 mmol)[4-(2-methoxy-phenyl)-piperidin-1-yl]-(1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanonehydrochloride, 0.026 ml (0.19 mmol) triethylamine and 0.023 g (0.77mmol) paraformaldehyde in 2 ml methanol was heated at reflux for 1 h.The reaction mixture was cooled to 0° C. on an ice-water bath andtreated with 0.0089 g (0.14 mmol) sodium cyanoborohydride. Aftercompleted addition the mixture was allowed to warm to room temperatureand stirred for 2 h. Quenching with water and dilution with 2 M aqueoussodium carbonate solution was followed by extraction withdichloromethane (2×50 ml). The combined organic layers were dried oversodium sulfate, concentrated in vacuo and purified byflash-chromatography (aminopropyl-modified silica gel, n-heptane/ethylacetate) to give the title compound (0.031 g, 82%) as an off-whitesolid.

MS m/e (%): 404 (M+H⁺, 100).

Examples of Compounds of Formula I-c Example 131Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-piperazin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 1-Phenyl-piperazine (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 410.6 (M+H⁺).

Example 132Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 1-(2-Methoxy-phenyl)-piperazine (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 440.6 (M+H⁺).

Example 133Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 1-(4-Methoxy-phenyl)-piperazine (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 440.6 (M+H⁺).

Example 134

Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-phenyl)-piperazin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 1-(2-Chloro-phenyl)-piperazine (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 444.5 (M+H⁺).

Example 135Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-chloro-phenyl)-piperazin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 1-(4-Chloro-phenyl)-piperazine (commercially available),Acid: 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 444.5 (M+H⁺).

Example 136 (6-Chloro-1H-indol-3-yl)-(4-phenyl-piperazin-1-yl)-methanone

Amide coupling according to general procedure I:

Amine: 1-Phenyl-piperazine (commercially available),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 340.4 (M+H⁺).

Example 137(6-Chloro-1H-indol-3-yl)-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(2-chloro-6-nitro-phenyl)-piperazine with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 419.4 (M+H⁺).

Example 138(6-Chloro-1H-indol-3-yl)-[4-(2,6-dichloro-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(2,6-dichloro-phenyl)-piperazine with 6-chloro-1H-indole-3-carboxylicacid gave the title compound.

ES-MS m/e (%): 408.4 (M+H⁺).

Example 139(6-Chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazine with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 398.4 (M+H⁺).

Example 140(6-Chloro-1H-indol-3-yl)-[4-(2-nitro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(2-nitro-4-trifluoromethyl-phenyl)-piperazine with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 453.4 (M+H⁺).

Example 141(6-Chloro-1H-indol-3-yl)-[4-(2-chloro-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(2-chloro-phenyl)-piperazine, with 6-chloro-1H-indole-3-carboxylicacid gave the title compound

ES-MS m/e (%): 374.4 (M+H⁺).

Example 142[4-(2-Amino-6-chloro-phenyl)-piperazin-1-yl]-(6-chloro-1H-indol-3-yl)-methanone

Following general procedure I, the coupling of3-chloro-2-piperazin-1-yl-phenylamine (described in Tetrahedron Letters(2001), 42(9), 1645-1646), with 6-chloro-1H-indole-3-carboxylic acidgave the title compound

ES-MS m/e (%): 389.4 (M+H⁺).

Example 143(6-Chloro-1H-indol-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(4-methoxy-phenyl)-piperazine with 6-chloro-1H-indole-3-carboxylicacid gave the title compound

ES-MS m/e (%): 370.4 (M+H⁺).

Example 144(6-Chloro-1H-indol-3-yl)-[4-(3-methoxy-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(3-methoxy-phenyl)-piperazine with 6-chloro-1H-indole-3-carboxylicacid gave the title compound

ES-MS m/e (%): 370.4 (M+H⁺).

Example 145(6-Chloro-1H-indol-3-yl)-[4-(2-nitro-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(2-nitro-phenyl)-piperazine with 6-chloro-1H-indole-3-carboxylic acidgave the title compound.

ES-MS m/e (%): 385.4 (M+H⁺).

Example 146(6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(2-methoxy-phenyl)-piperazine with 6-chloro-1H-indole-3-carboxylicacid gave the title compound.

ES-MS m/e (%): 370.4 (M+H⁺).

Example 147(6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(4-fluoro-phenyl)-piperazine with 6-chloro-1H-indole-3-carboxylic acidgave the title compound

ES-MS m/e (%): 358.4 (M+H⁺).

Example 148(6-Chloro-1H-indol-3-yl)-[4-(3-fluoro-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(3-fluoro-phenyl)-piperazine with 6-chloro-1H-indole-3-carboxylic acidgave the title compound.

ES-MS m/e (%): 358.4 (M+H⁺).

Example 149

Chloro-4-[4-(6-chloro-1H-indole-3-carbonyl)-piperazin-1-yl]-benzonitrile

Following general procedure I, the coupling of (commercially available)3-chloro-4-piperazin-1-yl-benzonitrile with6-chloro-1H-indole-3-carboxylic acid gave the title compound

ES-MS m/e (%): 399.4 (M+H⁺).

Example 150(6-Chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 1-(2-Ethoxy-phenyl)-piperazine (commercially available),Acid: 6-Chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 384.0 (M+H⁺).

Example 1512-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 455.2 (M+H⁺).

Example 1522-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Amide coupling according to general procedure I:

Amine: 1-(2-Ethoxy-phenyl)-piperazine (commercially available),Acid: 6-Chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 469.1 (M+H⁺).

Example 1532-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 510.6 (M+H⁺).

Example 1542-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 524.6 (M+H⁺).

Example 1552-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)N¹,N¹-dimethyl-ethane-1,2-diamine gave the title compound.

ES-MS m/e (%): 499.6 (M+H⁺).

Example 1562-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)N¹,N¹-dimethyl-ethane-1,2-diamine gave the title compound.

ES-MS m/e (%): 512.6 (M+H⁺).

Example 1572-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid (prepared described herein) with (commercially available) ammoniain THF, gave the title compound.

ES-MS m/e (%): 427.5 (M+H⁺).

Example 1582-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperidine-1-carbonyl]-5-methyl-indol-1-yl}-N,N-dimethyl-acetamide

Amide coupling according to general procedure I:

Amine: 1-(2-Methoxy-phenyl)-piperazine (commercially available),Acid: 6-Chloro-1-dimethylcarbamoylmethyl-5-methyl-1H-indole-3-carboxylicacid,

ES-MS m/e (%): 469.3 (M+H⁺).

Example 1592-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanonehydrochloride

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid (prepared described herein) with (commercially available))piperazine-1-carboxylic acid tert-butyl ester gave, after treatment withHCl, the title compound.

ES-MS m/e (%): 496.5 (M+H⁺).

Example 1602-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamidehydrochloride

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid (prepared herein) with (commercially available)(2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, aftertreatment with HCl, the title compound.

ES-MS m/e (%): 484.5 (M+H⁺).

Example 161N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamidehydrochloride{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 428.5 (M+H⁺).

N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamidehydrochloride

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid with (commercially available) (2-amino-ethyl)-carbamic acidtert-butyl ester gave, after treatment with HCl, the title compound.

ES-MS m/e (%): 470.6 (M+H⁺).

Example 1622-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 441.5 (M+H⁺).

Example 163[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone(prepared herein) with (commercially available)(2-chloro-ethyl)-dimethyl-amine gave the title compound.

ES-MS m/e (%): 441.5 (M+H⁺).

Example 164[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone(prepared herein) with (commercially available) 2-chloro-ethylamine gavethe title compound.

ES-MS m/e (%): 413.4 (M+H⁺).

Example 165[6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone

Analogous to general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone(prepared herein) with (commercially available)(2-chloro-ethyl)-methyl-amine gave the title compound.

ES-MS m/e (%): 427.5 (M+H⁺).

Example 166[6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)(2-chloro-ethyl)-methyl-amine gave the title compound.

ES-MS m/e (%): 441.5 (M+H⁺).

Example 1672-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 440.0 (M+H⁺).

2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide

Analogous to general procedure I, the coupling of{6-chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid with (commercially available) (2-amino-ethyl)-methyl-carbamic acidtert-butyl ester gave, after treatment with HCl and neutralisation, thetitle compound.

ES-MS m/e (%): 498.5 (M+H⁺).

Example 168[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)(2-chloro-ethyl)-dimethyl-amine gave the title compound.

ES-MS m/e (%): 455.3 (M+H⁺).

Example 169(6-Chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(2-fluoro-phenyl)-piperazine (described herein) with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 358.0 (M+H⁺).

Example 170[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-ethylamine gave the title compound.

ES-MS m/e (%): 401.2 (M+H⁺).

Example 171[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)(2-chloro-ethyl)-dimethyl-amine gave the title compound.

ES-MS m/e (%): 429.3 (M+H⁺).

Example 1722-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.

ES-MS m/e (%): 498.3 (M+H⁺).

Example 1732-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid, with (commercially available) N¹,N¹-dimethyl-ethane-1,2-diaminegave the title compound.

ES-MS m/e (%): 486.3 (M+H⁺).

Example 1742-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N,N-dimethyl-acetamide gave the title compound.

ES-MS m/e (%): 443.2 (M+H⁺).

Example 1752-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid (preparation described herein), with (commercially available)ammonia in THF gave the title compound.

ES-MS m/e (%): 415.2 (M+H⁺).

Example 1762-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)2-chloro-N-methyl-acetamide gave the title compound.

ES-MS m/e (%): 429.2 (M+H⁺).

Example 1772-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with (commercially available)bromo-acetic acid gave the title compound.

ES-MS m/e (%): 414.0 (M−H⁺).

2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid, with (commercially available) piperazine-1-carboxylic acidtert-butyl ester gave, after treatment with HCl and neutralisation, gavethe title compound.

ES-MS m/e (%): 484.2 (M+H⁺).

Example 1782-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide

Following general procedure II, the alkylation of{6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid (preparation described herein), with (commercially available)(2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, aftertreatment with HCl and neutralisation, the title compound.

ES-MS m/e (%): 472.2 (M+H⁺).

Example 179N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide

Following general procedure I, the coupling of{6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-aceticacid (preparation described herein), with (commercially available)(2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatmentwith HCl and neutralisation, the title compound.

ES-MS m/e (%): 458.2 (M+H⁺).

Example 1802-{6-Chloro-3-[4-(2-methoxymethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide4-(2-Methoxymethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

A solution of (commercially available)4-(2-hydroxymethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl esterand (1 eq) MeI dissolved in THF was treated with NaH (2 eq) and stirredat RT for 2 h. After work-up, the crude solid was purified by SiO₂chromatography (Ethyl acetate-Heptane 1:4) to give the title compound.

ES-MS m/e (%): 307.5 (M+H⁺).

1-(2-Methoxymethyl-phenyl)-piperazine

A solution of 4-(2-methoxymethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (prepared as described herein below) in dioxan wastreated with 4 eq. of 4M HCl in dioxane and stirred at RT for 16 h.After neutralization, the mixture was completely evaporated to give thecrude title compound.

ES-MS m/e (%): 207.1 (M+H⁺).

2-{6-Chloro-3-[4-(2-methoxymethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Following general procedure I, the coupling of1-(2-methoxymethyl-phenyl)-piperazine, with6-chloro-1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-1H-indole-3-carboxylicacid (preparation described herein) gave the title compound.

ES-MS m/e (%): 512.3 (M+H⁺).

Example 1812-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Following general procedure I, the coupling of (commercially available)1-(2-trifluoromethyl-phenyl)-piperazine, with6-chloro-1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-1H-indole-3-carboxylicacid (preparation described herein) gave the title compound.

ES-MS m/e (%): 536.2 (M+H⁺).

Example 1822-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamide

Following general procedure I, the coupling of (commercially available)1-pyridin-2-yl-piperazine, with6-chloro-1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-1H-indole-3-carboxylicacid (preparation described herein) gave the title compound.

ES-MS m/e (%): 469.2 (M+H⁺).

Example 1832-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamide

Following general procedure I, the coupling of (commercially available)1-(2,4-difluoro-phenyl)-piperazine with 6-chloro-1H-indole-3-carboxylicacid gave the title compound.

ES-MS m/e (%): 376.1 (M+H⁺).

Example 184(6-Chloro-1H-indol-3-yl)-[4-(3-methyl-pyridin-2-yl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(3-methyl-pyridin-2-yl)-piperazine with6-chloro-1H-indole-3-carboxylic acid gave the title compound. ES-MS m/e(%): 355.1 (M+H⁺).

Example 185(6-Chloro-1H-indol-3-yl)-[4-(3,5-dichloro-pyridin-4-yl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(3,5-dichloro-pyridin-4-yl)-piperazine with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 409.0 (M+H⁺).

Example 186(6-Chloro-1H-indol-3-yl)-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone

Following general procedure I, the coupling of (commercially available)1-(3-trifluoromethyl-pyridin-2-yl)-piperazine with6-chloro-1H-indole-3-carboxylic acid gave the title compound.

ES-MS m/e (%): 409.1 (M+H⁺).

Example 1872-[4-(6-Chloro-1H-indole-3-carbonyl)-piperazin-1-yl]-nicotinonitrile

Following general procedure I, the coupling of (commercially available)2-piperazin-1-yl-nicotinonitrile with 6-chloro-1H-indole-3-carboxylicacid gave the title compound.

ES-MS m/e (%): 366.1 (M+H⁺).

Example 188(6-Chloro-1H-indol-3-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone

Following general procedure I, the coupling of (commercially available)1-pyridin-2-yl-piperazine with 6-chloro-1H-indole-3-carboxylic acid gavethe title compound.

ES-MS m/e (%): 341.1 (M+H⁺).

Example 189(6-Chloro-1H-indol-3-yl)-(4-thiazol-2-yl-piperazin-1-yl)-methanone

Following general procedure I, the coupling of (commercially available)1-thiazol-2-yl-piperazine with 6-chloro-1H-indole-3-carboxylic acid gavethe title compound.

ES-MS m/e (%): 347.0 (M+H⁺).

Example 1902-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(2,4-difluoro-phenyl)-piperazine, with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein below) gave the title compound.

ES-MS m/e (%): 447.1 (M+H⁺).

Example 1912-[6-Chloro-3-(2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-carbonyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl, with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 413.1 (M+H⁺).

Example 1922-{6-Chloro-3-[4-(3-methyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(3-methyl-pyridin-2-yl)-piperazine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 426.2 (M+H⁺).

Example 1932-{6-Chloro-3-[4-(3,5-dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(3,5-dichloro-pyridin-4-yl)-piperazine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 480.1 (M+H⁺).

Example 1942-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-pyridin-2-yl-piperazine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 412.1 (M+H⁺).

Example 1952-[6-Chloro-3-(4-thiazol-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-thiazol-2-yl-piperazine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 418.1 (M+H⁺).

Example 1962-{6-Chloro-3-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(3-trifluoromethyl-pyridin-2-yl)-piperazine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 480.1 (M+H⁺).

Example 1972-{6-Chloro-3-[4-(3-cyano-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)2-piperazin-1-yl-nicotinonitrile with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 437.1 (M+H⁺).

Example 198[1-((S)-2-Amino-propyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

Following general procedure II, the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with methanesulfonic acid(S)-2-tert-butoxycarbonylamino-propyl ester (described in WO 2005100321)gave, after treatment with TFA and subsequent neutralization, the titlecompound.

ES-MS m/e (%): 415.2 (M+H⁺).

Example 199(6-Chloro-1-(S)-1-piperidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

In analogy to the reaction conditions used in general procedure II, thealkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with methanesulfonic acid(S)-3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butylester (described in JP 2001278872), followed by treatment with TFA andsubsequent neutralisation, gave the title compound in 56% yield.

ES-MS m/e (%): 455.3 (M+H⁺).

Example 200(6-Chloro-1-(S)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

In analogy to the preparation of(6-chloro-1-(S)-1-piperidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(described herein), the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with(S)-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butylester (described in Tetrahedron: Asymmetry (1997), 8(13), 2209-2213),followed by treatment with TFA and subsequent neutralisation, gave thetitle compound in 55% yield.

ES-MS m/e (%): 441.3 (M+H⁺).

Example 201(6-Chloro-1-(RS)-1-pyrrolidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

In analogy to the preparation of(6-chloro-1-(S)-1-piperidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(described herein), the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with(RS)-3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butylester (described in WO 9742189), followed by treatment with TFA andsubsequent neutralisation, gave the title compound in 51% yield.

ES-MS m/e (%): 441.3 (M+H⁺).

Example 202[6-Chloro-1-((S)-1-methyl-piperidin-3-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

A solution of(6-chloro-1-(S)-1-piperidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein below) in MeOH was treated with aq. H₂CO(1.5 eq) and AcOH (1.1 eq) and stirred for 15 min at RT, then treatedwith NaCNBH₃ (1.1 eq) and stirred at RT for 1 h. Concentration andpurification by prep HPLC gave the desired product. in 71% yield.

ES-MS m/e (%): 469.3 (M+H⁺).

Example 203[6-Chloro-1-((S)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

(6-Chloro-1-(S)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), was treated with a 37% aq. solution offormaldehyde (1.05 eq.), acetic acid (1.05 eq.) and sodiumcyanoborohydride (1.0 eq.) in MeOH at RT for 2 h to give afterpurification by prep. HPLC the title compound in 62% yield.

ES-MS m/e (%): 455.3 (M+H⁺).

Example 204[6-Chloro-1-((RS)-1-methyl-pyrrolidin-3-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

Following the procedure described in the preparation of(6-chloro-1-(S)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(described herein), the alkylation of(6-chloro-1-(RS)-1-pyrrolidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein) gave the title compound in 64% yield.

ES-MS m/e (%): 455.3 (M+H⁺).

Example 2052-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(2,4-difluoro-phenyl)-piperazine, with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid gave thetitle compound.

ES-MS m/e (%): 461.2 (M+H⁺).

Example 2062-[6-Chloro-3-(2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl, with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 427.2 (M+H⁺).

Example 2072-{6-Chloro-3-[4-(3-methyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(3-methyl-pyridin-2-yl)-piperazine with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 440.2 (M+H⁺).

Example 2082-{6-Chloro-3-[4-(3,5-dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(3,5-dichloro-pyridin-4-yl)-piperazine with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 494.1 (M+H⁺).

Example 2092-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-pyridin-2-yl-piperazine with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 426.2 (M+H⁺).

Example 2102-[6-Chloro-3-(4-thiazol-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)1-thiazol-2-yl-piperazine with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 432.2 (M+H⁺).

Example 2112-{6-Chloro-3-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(3-trifluoromethyl-pyridin-2-yl)-piperazine with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid gave thetitle compound. ES-MS m/e (%): 494.2 (M+H⁺).

Example 2122-{6-Chloro-3-[4-(3-cyano-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)2-piperazin-1-yl-nicotinonitrile with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 451.2 (M+H⁺).

Example 2132-[6-Chloro-3-(4-pyrimidin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide

Following general procedure I, the coupling of (commercially available)2-piperidin-4-yl-pyrimidine with6-chloro-1-dimethylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 427.2 (M+H⁺).

Example 214(6-Chloro-1-(R)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

In analogy to the preparation of(6-chloro-1-(S)-1-piperidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(described herein), the alkylation of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), with(R)-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butylester (described in Tetrahedron: Asymmetry (1997), 8(13), 2209-2213),followed by treatment with TFA and subsequent neutralisation, gave thetitle compound in 26% yield.

ES-MS m/e (%): 441.3 (M+H⁺).

Example 215[6-Chloro-1-((R)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

Following the procedure described in the preparation of[6-chloro-1-((S)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone,the alkylation of(6-chloro-1-(R)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein) gave the title compound.

ES-MS m/e (%): 455.3 (M+H⁺)

Example 216(6-Chloro-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone

The title compound was obtained as a white solid in 16% yield accordingto the procedure described for the preparation of(6-chloro-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanoneusing 1-(2-methoxy-phenyl)-piperazine instead of4-(2-methoxy-phenyl)-piperidine.

MS m/e (%): 382 (M−H⁺, 100).

Example 217N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-acetamide[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone

To a solution of(6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanonein dry DMF under argon at 0° C. was added (1.1 eq) NaH. The reactionmixture was stirred for 1 h at 0° C.2,2-Dioxo-2λ⁶-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester(1.1 eq) (described in WO 2003037327) was added, and the reactionmixture was stirred for 2 h at RT. After evaporation of DMF,redissolution in dioxan, addition of 5 eq. of HCl (4.0M solution indioxane) and a few drops of water, the reaction mixture was stirred for2 h at 50° C.; LC-MS showed complete conversion to the crude product.

Concentration in vacuo, redissolution in EtOAc, and washing with 1NNaHCO₃, gave after concentration, the crude product which was purifiedby SiO₂ gel chromatography with CH₂Cl₂/MeOH to give the title compoundin 55% yield.

ES-MS m/e (%): 401.2 (M+H⁺).

N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-acetamide

[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone,was treated with acetylchloride (1.05 eq) and triethylamine (1.05 eq) inCH₂Cl₂ under argon at RT for 2 h to give after purification by prep.HPLC the title compound.

ES-MS m/e (%): 443.2 (M+H⁺).

Example 218N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-methanesulfonamide

[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone(preparation described herein), was treated with mesylchloride (1.05 eq)and triethylamine (1.05 eq) in CH₂Cl₂ under argon at RT. to give afterpurification by prep. HPLC the title compound.

ES-MS m/e (%): 479.1 (M+H⁺).

Example 219N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-N-methyl-acetamide

N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-acetamide(preparation described herein) was treated with NaH (1.05 eq), MeI (1.05eq) in dry DMF under argon at RT for 2 h to give after purification byprep. HPLC the title compound.

ES-MS m/e (%): 457.1 (M+H⁺).

Example 220N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-N-methyl-acetamide

N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-methanesulfonamide(preparation described herein), was treated with NaH (1.05 eq), MeI(1.05 eq) in dry DMF under argon at RT for 2 h to give afterpurification by prep. HPLC the title compound.

ES-MS m/e (%): 493.1 (M+H⁺).

Example 2212-{6-Chloro-3-[4-(6-chloro-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(6-chloro-pyridin-2-yl)-piperazine, with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 446.1 (M+H⁺).

Example 2222-{6-Chloro-3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(5-trifluoromethyl-pyridin-2-yl)-piperazine, with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 480.1 (M+H⁺).

Example 2232-[6-Chloro-3-(4-thieno[2,3-c]pyridin-7-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)7-piperazin-1-yl-thieno[2,3-c]pyridine, with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 468.1 (M+H⁺).

Example 2242-[6-Chloro-3-(4-thieno[3,2-c]pyridin-4-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)4-piperazin-1-yl-thieno[3,2-c]pyridine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 468.1 (M+H⁺).

Example 2252-{6-Chloro-3-[4-(3-iodo-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(3-iodo-pyridin-2-yl)-piperazine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid gave thetitle compound.

ES-MS m/e (%): 538.0 (M+H⁺).

Example 2262-{6-Chloro-3-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 514.1 (M+H⁺).

Example 2272-[4-(6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carbonyl)-piperazin-1-yl]-nicotinicacid

Following general procedure I, the coupling of (commercially available)2-piperazin-1-yl-nicotinic acid with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 456.1 (M+H⁺).

Example 2282-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide

Following general procedure I, the coupling of (commercially available)1-(2,4-difluoro-phenyl)-piperazine with6-chloro-1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-1H-indole-3-carboxylicacid (prepared as described herein) gave the title compound.

ES-MS m/e (%): 504.3 (M+H⁺).

Example 2292-{6-Chloro-3-[4-(4-fluoro-2-methanesulfonyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide

Following general procedure I, the coupling of (commercially available)1-(4-fluoro-2-methanesulfonyl-phenyl)-piperazine with6-chloro-1-methylcarbamoylmethyl-1H-indole-3-carboxylic acid (preparedas described herein) gave the title compound.

ES-MS m/e (%): 506.9 (M+H⁺).

Example of a Compound of Formula I-d Example 230(6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-4-oxy-piperazin-1-yl]-methanone

Amide coupling according to general procedure I:

Amine: 1-(2-Methoxy-phenyl)-piperazine 1-oxide (described in EP126480),Acid: 6-chloro-1H-indole-3-carboxylic acid,

ES-MS m/e (%): 386.4 (M+H⁺).

1. A compound of formula I:

wherein R¹ is H, C₁₋₆-alkyl substituted by CN, C₁₋₆-alkoxy, OH, halo, orNR^(i)R^(ii), C₂₋₆-alkyl, aryl, 5 or 6 membered heteroaryl orsulfonylaryl each of which is optionally substituted by one or more B,—(CH₂)_(m)—R^(a) wherein R^(a) is: CN, OR^(i), NR^(i)R^(ii), orC₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6membered heteroaryl each of which is optionally substituted by one ormore B, or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), whereinR^(b) is: C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl,—(CH₂)_(m)—NR^(iii)R^(iv), NR^(i)R^(ii), or C₃₋₆-cycloalkyl, 4 to 7membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each ofwhich is optionally substituted by one or more B, or R¹ and R³ togetherwith the indole ring to which they are attached form a 5 or 6 memberedheterocycloalkyl which is optionally substituted by ═O, C(O)O—C₁₋₆-alkylor C₁₋₆-alkyl; there is one or more R², wherein each R² is the same ordifferent, R² is one or more H, OH, halo, CN, nitro, C₁₋₆-alkoxy,—O—CH₂—C₂₋₆-alkenyl, benzyloxy, C₁₋₆-haloalkoxy, or C₁₋₆-alkyloptionally substituted by —NR^(ii)R^(v) or halo, or two R² together withthe indole ring to which they are attached form an oxo or dioxo bridge;R³ is H, F, —(CO)—R^(c), wherein R^(c) is: C₁₋₆-alkyl,—(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), or 5 or 6 memberedheterocycloalkyl optionally substituted by C₁₋₆-alkyl, or C₁₋₆-alkylwhich is optionally substituted by halo, NR^(i)R^(ii), NR^(iii)R^(iv),—O(CO)—C₁₋₆-alkyl, or —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyloptionally substituted by halo or nitro, or R^(d) is aryl or a 5 or 6membered heteroaryl, each of which is optionally substituted by halo,nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl; wherein R¹, R², and R³ are notsimultaneously H; A is selected from the group consisting of (a), (a′),(b), (c) and (d):

wherein R⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy or aryloptionally substituted by halo, C₁₋₆-alkoxy, or CN, or aryl, 5 or 6membered heteroaryl, benzyl, aryloxy or a 9 or 10-membered bicyclicheteroaryl ring, each of which is optionally substituted by CN, halo,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl, nitro, hydroxyl, NR^(i)R^(ii),NR^(iii)R^(iv), C₁₋₆-alkoxy-C₁₋₆-alkylene, S(O)₂—C₁₋₆-alkyl, orC₁₋₆-haloalkoxy, or by an oxo or dioxo bridge; R⁶ is C₂₋₆-alkyl,—C(O)—R^(f) wherein R^(f) is an aryl group substituted by halo,C₁₋₆-alkoxy, or CN, aryl, 5 or 6 membered heteroaryl, or a 9 or10-membered bicyclic heteroaryl ring each of which is optionallysubstituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl, CN, nitro,NR^(i)R^(ii), NR^(iii)R^(iv), C₁₋₆-alkoxy-C₁₋₆-alkylene, COOH,S(O)₂—C₁₋₆-alkyl, hydroxyl, or C₁₋₆-haloalkoxy, or by an oxo or dioxobridge; B is halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionally substitutedby CN, halo or C₁₋₆-alkoxy, C₁₋₆-haloalkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)NR^(i)R^(ii),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, —S(O)₂—NR^(i)R^(ii), or(CR^(iii)R^(iv))_(n)-phenyl, or (CR^(iii)R^(iv))_(n)-5 or 6 memberedheteroaryl wherein the phenyl or 5 or 6 membered heteroaryl moiety isoptionally substituted by one or more substituent(s) selected from thegroup consisting of: halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionallysubstituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and —S(O)₂—NR^(i)R^(ii); R^(i) andR^(ii) are each independently H, C₁₋₆-alkyl, C₁₋₆-alkyl-NR^(iii)R^(iv),—(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl,—S(O)₂—C₁₋₆-alkyl or —S(O)₂—NR^(iii)R^(iv); R^(iii) and R^(iv) are eachindependently H or C₁₋₆-alkyl; m is 1 to 6; and n is 0 to 4; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein R¹ is H, C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,aryl, 5 or 6 membered heteroaryl or sulfonylaryl each of which isoptionally substituted by one or more B, —(CH₂)_(m)—R^(a) wherein R^(a)is: CN, OR¹, NR^(i)R^(ii), or C₃₋₆-cycloalkyl, 4 to 7membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each ofwhich is optionally substituted by one or more B, or—(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl, —(CH₂)_(m)—NR^(iii)R^(iv),NR^(i)R^(ii), or C₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl,aryl, or 5 or 6 membered heteroaryl each of which is optionallysubstituted by one or more B, or R¹ and R³ together with the indole ringto which they are attached form a 5 or 6 membered heterocycloalkyl whichis optionally substituted by (CO); there is one or more R², wherein eachR² is the same or different, R² is one or more H, OH, halo, CN, nitro,C₁₋₆-alkyl optionally substituted by —NR^(iii)R^(iv), C₁₋₆-alkoxy,—O—CH₂—C₂₋₆-alkenyl, or benzyloxy, or two R² together with the indolering to which they are attached form an oxo or dioxo bridge; R³ is H,halo, —(CO)—R^(c), wherein R^(c) is: C₁₋₆-alkyl,—(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), or 5 or 6 memberedheterocycloalkyl optionally substituted by C₁₋₆-alkyl, or C₁₋₆-alkyl oraryl, each of which is optionally substituted by halo,—O(CO)—C₁₋₆-alkyl, or —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyloptionally substituted by halo or nitro, or R^(d) is aryl or a 5 or 6membered heteroaryl, each of which is optionally substituted by halo,nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl; wherein R¹, R², and R³ are notsimultaneously H; A is selected from the group consisting of (a), (b),(c) and (d):

wherein R⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy or aryloptionally substituted by halo, C₁₋₆-alkoxy, or CN, or aryl, 5 or 6membered heteroaryl, benzyl, aryloxy or a 9 or 10-membered bicyclicheteroaryl ring each of which is optionally substituted by CN, halo,C₁₋₆-alkyl, C₁₋₆-alkoxy, or C₁₋₆-haloalkyl, or by a dioxo bridge; R⁶ isC₁₋₆-alkyl, —C(O)—R^(f) wherein R^(f) is an aryl group optionallysubstituted by halo, C₁₋₆-alkoxy, or CN, or aryl, 5 or 6 memberedheteroaryl, or a 9 or 10-membered bicyclic heteroaryl ring each of whichis optionally substituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkyl, or CN or by a dioxo bridge; B is halo, CN, NR^(i)R^(ii),C₁₋₆-alkyl optionally substituted by CN, halo or C₁₋₆-alkoxy,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl,—C(O)NR^(i)R^(ii) —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl,—S(O)₂—NR^(i)R^(ii), or (CR^(iii)R^(iv))_(n)-phenyl, or(CR^(iii)R^(iv))_(n)-5 or 6 membered heteroaryl wherein the phenyl or 5or 6 membered heteroaryl moiety is optionally substituted by one or moresubstituent(s) selected from the group consisting of: halo, CN,NR^(i)R^(ii), C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy,C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl,—C(O)—NR^(i)R^(ii), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, and—S(O)₂—NR^(i)R^(ii); R^(i) and R^(ii) are each independently H,C₁₋₆-alkyl, C₁₋₆-alkyl-NR^(iii)R^(iv), —(CO)O—C₁₋₆-alkyl,—C(O)—NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl or—S(O)₂—NR^(iii)R^(iv); R^(iii) and R^(iv) are each independently H orC₁₋₆-alkyl; m is 1 to 6; and n is 0 to 4; or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 1, wherein R¹ is H,C₁₋₆-alkyl optionally substituted by CN or C₁₋₆-alkoxy, aryl, 5 or 6membered heteroaryl, sulfonylaryl, —(CH₂)_(m)—R^(a) wherein R^(a) isC₃₋₆-cycloalkyl, 5 or 6 membered-heterocycloalkyl, aryl, or 5 or 6membered heteroaryl each of which is optionally substituted by one ormore substituents selected from the group consisting of: halo, CN,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy, —C(O)O—C₁₋₆-alkyl, and phenyloptionally substituted by halo, C₁₋₆-alkyl, C₁₋₆-haloalkyl orC₁₋₆-alkoxy, —(CH₂)_(m)—NR^(i)R^(ii), or —(CH₂)_(n)—(CO)—R^(b), whereinR^(b) is aryl or 5 or 6 membered-heterocycloalkyl; there is one or moreR², wherein each R² is the same or different, R² is one or more H, halo,CN, nitro, C₁₋₆-alkyl, C₁₋₆-alkoxy, —O—CH₂—C₂₋₆-alkenyl, or benzyloxy,or two R² together with the indole ring to which they are attached forman oxo or dioxo bridge; R³ is H, halo, —(CO)—R^(c), wherein R^(c) isC₁₋₆-alkyl, 5 or 6 membered heterocycloalkyl optionally substituted byC₁₋₆-alkyl, or R^(c) is —(CH₂)_(n)—NR^(i)R^(ii), or C₁₋₆-alkyl or aryl,each of which is optionally substituted by —O(CO)—C₁₋₆-alkyl, or—NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyl optionally substituted by haloor nitro, or R^(d) is aryl or a 5 or 6 membered heteroaryl, each ofwhich is optionally substituted by halo, nitro, C₁₋₆-alkyl orC₁₋₆-haloalkyl; R^(i) and R^(ii) are each independently selected from H,C₁₋₆-alkyl and —(CO)O—C₁₋₆-alkyl; m is 1 to 6; n is 0 to 4; wherein R¹,R², and R³ are not simultaneously H; A is selected from the groupconsisting of (a), (b), (c) and (d):

wherein R⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy or aryloptionally substituted by halo, or aryl, benzyl, aryloxy or a 9 or10-membered bicyclic heteroaryl ring each of which is optionallysubstituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy, or C₁₋₆-haloalkyl, or by adioxo bridge; and R⁶ is C₁₋₆-alkyl, —C(O)—R^(f) wherein R^(f) is an arylgroup optionally substituted by halo, or aryl, or a 9 or 10-memberedbicyclic heteroaryl ring each of which is optionally substituted byhalo, C₁₋₆-alkyl, C₁₋₆-alkoxy, or C₁₋₆-haloalkyl, or by a dioxo bridge;or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein: R¹ is H, C₁₋₆-alkyl substituted by NR^(i)R^(ii),—(CH₂)_(m)—R^(a) wherein R^(a) is: NR^(i)R^(ii), or 5 to 6membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each ofwhich is optionally substituted by one or more B, or—(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), wherein R^(b) is:C₁₋₆-alkyl, C₁₋₆-alkoxy, NR^(i)R^(ii), or 5 to 6membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each ofwhich is optionally substituted by one or more B, or R¹ and R³ togetherwith the indole ring to which they are attached form a 5 or 6 memberedheterocycloalkyl which is optionally substituted by ═O, C(O)O—C₁₋₆-alkylor C₁₋₆-alkyl; there is one or more R², wherein each R² is the same ordifferent, R² is one or more H, halo, or C₁₋₆-alkyl; R³ is H, orC₁₋₆-alkyl; wherein R¹, R², and R³ are not simultaneously H; A isselected from the group consisting of (a), (a′), (b), (c) and (d):

wherein R⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy, or aryloptionally substituted by halo, or aryl, 5 or 6 membered heteroaryl,benzyl, aryloxy or a 9 or 10-membered bicyclic heteroaryl ring, each ofwhich is optionally substituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkyl, nitro, hydroxyl, or C₁₋₆-haloalkoxy, or by an oxo ordioxo bridge; R⁶ is aryl, 5 or 6 membered heteroaryl, or a 9 or10-membered bicyclic heteroaryl ring each of which is optionallysubstituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl, CN, nitro,NR^(i)R^(ii), NR^(iii)R^(iv), C₁₋₆-alkoxy-C₁₋₆-alkylene, COOH, orS(O)₂—C₁₋₆-alkyl, or by an oxo or dioxo bridge; B is halo, C₁₋₆-alkyloptionally substituted by CN, halo or C₁₋₆-alkoxy, or C₁₋₆-alkoxy; R^(i)and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl or —S(O)₂—C₁₋₆-alkyl;R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl; m is 1 to 6;and n is 0 to 4; or a pharmaceutically acceptable salt thereof.
 5. Thecompound of claim 1, wherein R⁴ is not

optionally substituted by CN, halo, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-haloalkyl, nitro, hydroxyl, NR^(i)R^(ii), NR^(iii)R^(iv),C₁₋₆-alkoxy-C₁₋₆-alkylene, S(O)₂—C₁₋₆-alkyl, or C₁₋₆-haloalkoxy, or byan oxo or dioxo bridge.
 6. The compound of claim 1, having formula (I-a)or (I-a′):

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim6, wherein R¹ is H or —(CH₂)_(m)—R^(a) wherein R^(a) is aryl and m is 1to 6; there is one or more R², wherein each R² is the same or different,R² is one or more H or halo; R³ is H or C₁₋₆-alkyl; and wherein R¹, R²,and R³ are not simultaneously H; R⁴ is aryl which is optionallysubstituted by halo or C₁₋₆-alkoxy; or a pharmaceutically acceptablesalt thereof.
 8. The compound of claim 6, which is selected from thegroup consisting of:(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;(1-Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone;(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone;(6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone;and(1-Benzyl-2-methyl-1H-indol-3-yl)-(5-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone.9. The compound of claim 1, having formula (I-c)

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim9, wherein R¹ is H or C₁₋₆-alkyl substituted by NR^(i)R^(ii),—(CH₂)_(m)—R^(a) wherein R^(a) is: NR^(i)R^(ii), or 5 to 6membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each ofwhich is optionally substituted by one or more C₁₋₆-alkyl, or—(CH₂)_(n)—(CO)—R^(b), wherein R^(b) is: NR^(i)R^(ii), or 5 to 7membered-heterocycloalkyl which is optionally substituted by one or moreC₁₋₆-alkyl; there is one or more R², wherein each R² is the same ordifferent, R² is one or more H, halo or C₁₋₆-alkyl; R³ is H orC₁₋₆-alkyl; wherein R¹, R², and R³ are not simultaneously H; R⁶ is aryl,5 or 6 membered heteroaryl, or a 9 or 10-membered bicyclic heteroarylring each of which is optionally substituted by halo, C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-haloalkyl, CN, nitro, NR^(i)R^(ii), NR^(iii)R^(iv),C₁₋₆-alkoxy-C₁₋₆-alkylene, COOH, or S(O)₂—C₁₋₆-alkyl, or by an oxo ordioxo bridge; R^(i) and R^(ii) are each independently H, C₁₋₆-alkyl,C₁₋₆-alkyl-NR^(iii)R^(iv), —C(O)—C₁₋₆-alkyl, or —S(O)₂—C₁₋₆-alkyl;R^(iii) and R^(iv) are each independently H or C₁₋₆-alkyl; m is 1 to 6;and n is 0 to 4; or a pharmaceutically acceptable salt thereof.
 11. Thecompound of claim 9, which is selected from the group consisting of:(1-Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-piperazin-1-yl)-methanone;(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-phenyl)-piperazin-1-yl]-methanone;(1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-chloro-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-(4-phenyl-piperazin-1-yl)-methanone;(6-Chloro-1H-indol-3-yl)-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(2,6-dichloro-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-methanone;and(6-Chloro-1H-indol-3-yl)-[4-(2-nitro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone.12. The compound of claim 9, which is selected from the group consistingof:(6-Chloro-1H-indol-3-yl)-[4-(2-chloro-phenyl)-piperazin-1-yl]-methanone;[4-(2-Amino-6-chloro-phenyl)-piperazin-1-yl]-(6-chloro-1H-indol-3-yl)-methanone;(6-Chloro-1H-indol-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(3-methoxy-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(2-nitro-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(3-fluoro-phenyl)-piperazin-1-yl]-methanone;3-Chloro-4-[4-(6-chloro-1H-indole-3-carbonyl)-piperazin-1-yl]-benzonitrile;and(6-Chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone.13. The compound of claim 9, which is selected from the group consistingof:2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide;2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-5-methyl-indol-1-yl}-N,N-dimethyl-acetamide;2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanoneor hydrochloride salt thereof;2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamideor hydrochloride salt thereof;N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamideor hydrochloride salt thereof;[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;and[6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone.14. The compound of claim 9, which is selected from the group consistingof:[6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;[1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide;2-{6-Chloro-3-[4-(2-methoxymethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;and2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamide.15. The compound of claim 9, which is selected from the group consistingof:(6-Chloro-1H-indol-3-yl)-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(3-methyl-pyridin-2-yl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(3,5-dichloro-pyridin-4-yl)-piperazin-1-yl]-methanone;(6-Chloro-1H-indol-3-yl)-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone;2-[4-(6-Chloro-1H-indole-3-carbonyl)-piperazin-1-yl]-nicotinonitrile;(6-Chloro-1H-indol-3-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone;(6-Chloro-1H-indol-3-yl)-(4-thiazol-2-yl-piperazin-1-yl)-methanone;2-[6-Chloro-3-(2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-carbonyl)-indol-1-yl]-N-methyl-acetamide;2-{6-Chloro-3-[4-(3-methyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;2-{6-Chloro-3-[4-(3,5-dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;and2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide.16. The compound of claim 9, which is selected from the group consistingof:2-[6-Chloro-3-(4-thiazol-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;2-{6-Chloro-3-[4-(3-cyano-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;(6-Chloro-1-(S)-1-piperidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1-(RS)-1-pyrrolidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;[6-Chloro-1-((S)-1-methyl-piperidin-3-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;[6-Chloro-1-((RS)-1-methyl-pyrrolidin-3-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;2-[6-Chloro-3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;2-{6-Chloro-3-[4-(3-methyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;2-{6-Chloro-3-[4-(3,5-dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;and2-[6-Chloro-3-(4-thiazol-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide.17. The compound of claim 9, which is selected from the group consistingof:2-{6-Chloro-3-[4-(3-cyano-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;2-[6-Chloro-3-(4-pyrimidin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;(6-Chloro-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;2-{6-Chloro-3-[4-(6-chloro-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;2-{6-Chloro-3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;2-[6-Chloro-3-(4-thieno[2,3-c]pyridin-7-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;2-{6-Chloro-3-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;2-[4-(6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carbonyl)-piperazin-1-yl]-nicotinicacid;2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;and2-{6-Chloro-3-[4-(4-fluoro-2-methanesulfonyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide.18. The compound of claim 9, which is selected from the group consistingof:2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;[6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;and2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide.19. The compound of claim 9, which is selected from the group consistingof:2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone;2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;2-{6-Chloro-3-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;[1-((S)-2-Amino-propyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;(6-Chloro-1-(S)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;[6-Chloro-1-((S)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;and2-{6-Chloro-3-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide.20. The compound of claim 9, which is selected from the group consistingof:(6-Chloro-1-(R)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;[6-Chloro-1-((R)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-acetamide;N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-methanesulfonamide;N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-N-methyl-acetamide;N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-N-methyl-methanesulfonamide;2-[6-Chloro-3-(4-thieno[3,2-c]pyridin-4-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;and2-{6-Chloro-3-[4-(3-iodo-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide.21. The compound of claim 1, having formula (I-d)

or a pharmaceutically acceptable salt thereof.
 22. The compound of claim21, wherein: R¹ is H; R² is one or more halo; R³ is H; and wherein R¹,R², and R³ are not simultaneously H; R⁶ is aryl substituted byC₁₋₆-alkoxy; or a pharmaceutically acceptable salt thereof.
 23. Thecompound of claim 21, which is(6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-4-oxy-piperazin-1-yl]-methanone.24. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula I

wherein R¹ is H, C₁₋₆-alkyl substituted by CN, C₁₋₆-alkoxy, OH, halo, orNR^(i)R^(ii), C₂₋₆-alkyl, aryl, 5 or 6 membered heteroaryl orsulfonylaryl each of which is optionally substituted by one or more B,—(CH₂)_(m)—R^(a) wherein R^(a) is: CN, OR^(i), NR^(i)R^(ii), orC₃₋₆-cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6membered heteroaryl each of which is optionally substituted by one ormore B, or —(CH₂)_(n)—(CO)—R^(b) or —(CH₂)_(n)—(SO₂)—R^(b), whereinR^(b) is: C₁₋₆ alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkyl,—(CH₂)_(m)—NR^(iii)R^(iv), NR^(i)R^(ii), or C₃₋₆-cycloalkyl, 4 to 7membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each ofwhich is optionally substituted by one or more B, or R¹ and R³ togetherwith the indole ring to which they are attached form a 5 or 6 memberedheterocycloalkyl which is optionally substituted by ═O, C(O)O—C₁₋₆-alkylor C₁₋₆-alkyl; there is one or more R², wherein each R² is the same ordifferent, R² is one or more H, OH, halo, CN, nitro, C₁₋₆-alkoxy,—O—CH₂—C₂₋₆-alkenyl, benzyloxy, C₁₋₆-haloalkoxy, or C₁₋₆-alkyloptionally substituted by —NR^(ii)R^(v) or halo, or two R² together withthe indole ring to which they are attached form an oxo or dioxo bridge;R³ is H, F, —(CO)—R^(c), wherein R^(c) is: C₁₋₆-alkyl,—(CH₂)_(n)—NR^(i)R^(ii), —(CH₂)_(n)—NR^(iii)R^(iv), or 5 or 6 memberedheterocycloalkyl optionally substituted by C₁₋₆-alkyl, or C₁₋₆-alkylwhich is optionally substituted by halo, NR^(i)R^(ii), NR^(iii)R^(iv),—O(CO)—C₁₋₆-alkyl, or —NH(CO)R^(d), wherein R^(d) is C₁₋₆-alkyloptionally substituted by halo or nitro, or R^(d) is aryl or a 5 or 6membered heteroaryl, each of which is optionally substituted by halo,nitro, C₁₋₆-alkyl or C₁₋₆-haloalkyl; wherein R¹, R², and R³ are notsimultaneously H; A is selected from the group consisting of (a), (a′),(b), (c) and (d):

wherein R⁴ is —NH(CO)R^(e), wherein R^(e) is C₁₋₆-alkoxy or aryloptionally substituted by halo, C₁₋₆-alkoxy, or CN, or aryl, 5 or 6membered heteroaryl, benzyl, aryloxy or a 9 or 10-membered bicyclicheteroaryl ring, each of which is optionally substituted by CN, halo,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl, nitro, hydroxyl, NR^(i)R^(ii),NR^(iii)R^(iv), C₁₋₆-alkoxy-C₁₋₆-alkylene, S(O)₂—C₁₋₆-alkyl, orC₁₋₆-haloalkoxy, or by an oxo or dioxo bridge; R⁶ is C₂₋₆-alkyl,—C(O)—R^(f) wherein R^(f) is an aryl group substituted by halo,C₁₋₆-alkoxy, or CN, aryl, 5 or 6 membered heteroaryl, or a 9 or10-membered bicyclic heteroaryl ring each of which is optionallysubstituted by halo, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-haloalkyl, CN, nitro,NR^(i)R^(ii), NR^(iii)R^(iv), C₁₋₆-alkoxy-C₁₋₆-alkylene, COOH,S(O)₂—C₁₋₆-alkyl, hydroxyl, or C₁₋₆-haloalkoxy, or by an oxo or dioxobridge; B is halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionally substitutedby CN, halo or C₁₋₆-alkoxy, C₁₋₆-haloalkyl, C₁₋₆ alkoxy,C₁₋₆-haloalkoxy, C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)NR^(i)R^(ii),—C(O)—C₁₋₆-alkyl, —S(O)₂—C₁₋₆-alkyl, —S(O)₂—NR^(i)R^(ii), or(CR^(iii)R^(iv))_(n)-phenyl, or (CR^(iii)R^(iv))_(n)-5 or 6 memberedheteroaryl wherein the phenyl or 5 or 6 membered heteroaryl moiety isoptionally substituted by one or more substituent(s) selected from thegroup consisting of: halo, CN, NR^(i)R^(ii), C₁₋₆-alkyl optionallysubstituted by CN or C₁₋₆-alkoxy, C₁₋₆-alkoxy, C₁₋₆-haloalkoxy,C₃₋₆-cycloalkyl, —C(O)O—C₁₋₆-alkyl, —C(O)—NR^(i)R^(ii), —C(O)—C₁₋₆,—S(O)₂—C₁₋₆-alkyl, and —S(O)₂—NR^(i)R^(ii); R^(i) and R^(ii) are eachindependently H, C₁₋₆-alkyl, C₁₋₆-alkyl-NR^(iii)R^(iv),—(CO)O—C₁₋₆-alkyl, —C(O)—NR^(iii)R^(iv), —S(O)₂—C₁₋₆-alkyl or—S(O)₂—NR^(iii)R^(iv); R^(iii) and R^(iv) are each independently H orC₁₋₆-alkyl; m is 1 to 6; and n is 0 to 4; or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.